View
2
Download
0
Category
Preview:
Citation preview
HAL Id: hal-03028840https://hal.archives-ouvertes.fr/hal-03028840
Submitted on 1 Dec 2020
HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.
Recent advances in encapsulation of curcumin innanoemulsions: A review of encapsulation technologies,
bioaccessibility and applicationsTian Jiang, Wei Liao, Catherine Charcosset
To cite this version:Tian Jiang, Wei Liao, Catherine Charcosset. Recent advances in encapsulation of curcumin in na-noemulsions: A review of encapsulation technologies, bioaccessibility and applications. Food ResearchInternational, Elsevier, 2020, 132, pp.109035. �10.1016/j.foodres.2020.109035�. �hal-03028840�
Recent advances in encapsulation of curcumin in nanoemulsions: A review of
encapsulation technologies, bioaccessibility and applications
Tian JIANG, Wei LIAO, Catherine CHARCOSSET
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, 43 boulevard du
11 novembre 1918, F-69100, VILLEURBANNE, France
*Corresponding author: Tel: + 33 4 72 43 18 34
e-mail address: catherine.charcosset@univ-lyon1.fr
2
Abstract
Curcumin is widely acknowledged for its beneficial activities. However, its application has
remained challenging due to its low aqueous solubility, biochemical/ structural degradation
and poor bioavailability. For these reasons, many researches are aimed at overcoming these
limitations using lipid-based nanosystems to encapsulate curcumin, especially nanoemulsions.
This review highlights the theoretical aspects and recent advances of preparation technologies
(phase inversion temperature, phase inversion composition, ultrasonication, high pressure
homogenization and microfluidization) for encapsulation of curcumin in nanoemulsions.
Additionally, the specific factors in designing nanoemulsions systems that affect the chemical
stability and in vitro bioaccessibility of the encapsulated curcumin are discussed. Also, the
importance of nanoemulsions in improving antioxidant, anti-inflammatory and anticancer
activities of curcumin is underlined. Curcumin-loaded nanoemulsions preparation
technologies have been proposed to provide efficient, systematic, and practical protocols for
improved applications of curcumin. Additionally, key factors that influence curcumin delivery
include the nature of emulsifier, the type and the amount of carrier oil and
emulsifier-curcumin interactions. The pharmacological activities of curcumin including
antioxidant, anti-inflammatory and anticancer activities can be improved by nanoemulsions
resulting in better functional efficacy.
Keywords: Curcumin; Encapsulation; Nanoemulsions; Bioaccessibility; Applications
Abbreviations: TPA, 12-O-tetradecanoylphorbol-13-acetate; AP-1, ctivator protein-1;
CYP3A2, cytochrome P450 3A2; DME, direct membrane emulsification; DTAB,
dodecyltrimethylammonium bromide; GIT, gastrointestinal tract; GMO, glycerol monooleate;
GMS, glycerol monostearate; HPH, high pressure homogenization; HLB,
3
hydrophilic-lipophilic balance; IL-1β, interleukin-1β; LCT, long chain triacylglycerols; MCT,
medium chain triglycerides; NF-κB, nuclear factor κB; O/W, oil-in-water; Pgp,
p-glycoprotein; PIC, phase inversion composition; PIT, phase inversion temperature; PEG
400, polyethylene glycol; PME, premix membrane emulsification; ROS, reactive oxygen
species; SCT, short chain triacylglycerols; SGF, simulated gastric fluid; SIF, simulated
intestinal fluids; SSF, simulated saliva fluid; TABRS, thiobarbituric acid reactive substances;
TNF-α, tumor necrosis factor-α; W/O, water-in-oil; W/O/W, water-in-oil-in-water
1. Introduction
Curcumin is a natural low-molecular-weight (368.37g mol-1
) polyphenolic compound present
in the Curcuma longa (turmeric) rhizomes (Rafiee, Nejatian, Daeihamed, & Jafari, 2019).
Turmeric is a wide-spread spice, typical of Indian cooking, that also found use in traditional
Indian and Chinese medicines. Curcuminoids are the essential components of turmeric, which
are responsible for its yellow color. Turmeric rhizomes contain 3~5% four types of
curcuminoid derivatives including curcumin (77%), demethoxycurcumin (17%),
bisdemethoxycurcumin (3%) and cyclocurcumin, of which curcumin is the most important
bio-active constituent (Araiza-Calahorra, Akhtar, & Sarkar, 2018; Wakte et al., 2011).
Over the last few decades, curcumin has received considerable interest owing to its wide
range of pharmaceutical functions and biological features. Curcumin can be used as a
flavouring substance (bitter taste), as a food preservative, as a natural colorant (bright yellow
color) and as an antioxidant in various foods and beverages (Eybl, Kotyzova, & Koutensky,
2006; Wakte et al., 2011). Numerous studies have explored the applications of curcumin in
prophylaxis and treatment of a variety of inflammatory conditions including wound healing in
cutaneous (Mohanty, Das, & Sahoo, 2012; Nguyen et al., 2019; Phan, See, Lee, & Chan,
2001), excisional (Jagetia & Rajanikant, 2012; Mun et al., 2013) and chronic wounds (Kant et
al., 2015) and pro-inflammatory chronic diseases such as neurodegenerative diseases (Ghosh,
4
Banerjee, & Sil, 2015; Lv et al., 2014; Mourtas, Lazar, Markoutsa, Duyckaerts, &
Antimisiaris, 2014), cardiovascular diseases (Hasan et al., 2014; Sahebkar, 2015),
autoimmune diseases (Arora, Kuhad, Kaur, & Chopra, 2015; Rivera-Mancía, Lozada-García,
& Pedraza-Chaverri, 2015), gastrointestinal disorders (Morsy & El-Moselhy, 2013; Sah, Jha,
Sah, Shah, & Yadav, 2013) and psychological diseases (Jiang et al., 2013). Anti-cancer
activities of curcumin has also been extensively investigated and supporting evidences were
found for its potential use in chemoprevention and treatment of a wide variety of tumors
including breast (Liu & Ho, 2018), gastrointestinal (Jakubek et al., 2019; Rajasekaran, 2011),
melanoma (Wang et al., 2017) and sarcoma (M. Singh, Pandey, Karikari, Singh, & Rakheja,
2010). In spite of its excellent pharmacological benefits, researchers are still facing
difficulties related to its poor water solubility, chemical instability, photodegradation,
relatively high rate of metabolic degradation, rapid metabolism and rapid elimination from the
body, and low oral bioavailability (Hussain, Thu, Amjad, et al., 2017; Anand, Kunnumakkara,
Newman, & Aggarwal, 2007). Additionally, curcumin shows poor adsorption owing to its
lipophilic nature. To overcome these problems, new strategies have been employed for
improving its functional properties. Incorporation of curcumin into nanocarriers by different
techniques is a suitable and efficient option (Araiza-Calahorra et al., 2018; Hussain, Thu, Ng,
Khan, & Katas, 2017). Particularly, nanoemulsions have been described as excellent carriers
of lipophilic curcumin, to improve its stability and bioavailability.
In order to produce homogenous nanoemulsions, different processes (e.g., phase inversion
temperature, phase inversion composition, ultrasonication, high pressure homogenization and
microfluidization, etc.) have been developed. The preparation methods play an important role
in loading and encapsulation efficiency of curcumin, as well as droplet size after curcumin
incorporation. In this sense, suitable methodologies are needed to obtain nanoemulsions of
5
different sizes, structures and properties to achieve different applications. Also, a scale-up to a
higher level of production is necessary for industrial applications.
Hence, there is an essential need to extensively discuss the recent advances in different
methods for the preparation of curcumin-loaded nanoemulsions. Additionally, we present in
this review the specific factors in designing nanoemulsions system that affect the chemical
stability and in vitro bioaccessibility of the encapsulated curcumin. Finally, antioxidant,
anti-inflammatory and anticancer activities of such curcumin-loaded nanoformulations are
comprehensively underlined.
2. Properties of curcumin and their limitations in applications
2.1. Structural characteristics and chemistry properties of curcumin
Curcumin, also known as diferuloyl methane, is a symmetric molecule, with an ordered
crystal structure (Araiza-Calahorra et al., 2018; Sun et al., 2018). The structure of curcumin is
comprised of two aromatic rings with methoxyl and hydroxyl groups in the ortho position,
connected through a seven carbon chain consisting of an α, β-unsaturated β-diketone moiety
(Sahne, Mohammadi, Najafpour, & Moghadamnia, 2017). The molecular configuration of
curcumin can exist in the tautomeric forms keto and enol due to intramolecular hydrogen
atoms transfer at the β-diketone chain of curcumin. The structural features of curcumin are
illustrated in Fig. 1. Under slightly acidic and neutral conditions, the keto form is dominant.
However, in alkaline conditions, curcumin is present primarily in its enolic form (Ghosh et al.,
2015; Prasad, Gupta, Tyagi, & Aggarwal, 2014). In fact, the conformation of curcumin is
dependent of temperature, polarity and the properties of solvent (de Souza Ferreira & Bruschi,
2019).
Curcumin is a relatively hydrophobic molecule with a calculated log octanol/water partition
coefficient (logP) value of 3.2, which makes it practically insoluble in water and highly
soluble in lipid (Jamwal, 2018). It has adequate transmembrane permeability due to its
6
lipophilic nature (Hussain, Thu, Amjad, et al., 2017). However, curcumin is soluble in polar
solvents like methanol, acetone, ethanol and dimethyl sulfoxide (DMSO) (Araiza-Calahorra et
al., 2018). Besides, it is sensitive to environmental conditions, including elevated
temperatures, light, extreme pH, moisture, and oxygen. Under these conditions, the three
active sites (one diketone moiety, and two phenolic groups) of curcumin can suffer oxidation,
especially the phenol-OH functional group which is the most easily abstractable hydrogen
from curcumin. Then, the hydrogen donation reactions result in reversible and irreversible
nucleophilic addition (Michael reaction) reactions, hydrolysis, degradation and enzymatic
reactions (Priyadarsini, 2014). In general, the chemical degradation of curcumin in solution
leads to the formation a series of compounds, such as
trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal, vanillin, ferulic acid and
feruloylmethane (Typek et al., 2019).
2.2. Challenges for curcumin delivery
A major problem associated with the applications of curcumin is its poor bioavailability as a
result of the chemical stability, low water solubility as well as poor absorption and rapid
metabolism. The bioavailability of curcumin is determined by its bioaccessibility. Curcumin
needs to be bioaccessible to be absorbed by the gastrointestinal tract (GIT) epithelium cells
and then transported into the systemic circulation to exert biological activities. For that,
absorption of the curcumin in the GIT is crucial. However, most of curcumin through orally
consumed can not be absorbed into the small intestine epithelium cells due to the hydrophobic
property of curcumin. Even though part of curcumin can absorb into the epithelium cell, it can
be flushed back into the lumen through the efflux system (Sanidad, Sukamtoh, Xiao,
McClements, & Zhang, 2019). Moreover, after oral administration, most of curcumin is
degraded in tissues such as those of the liver and small intestine before entering the systemic
circulation because of the rapid metabolism (H. R. Park, Rho, & Kim, 2019).
7
Numerous studies have shown the low oral bioavailability of curcumin through evaluated the
level of curcumin or its metabolites in serum or tissue after administration. In animal studies,
Pan et al. (Pan, Huang, & Lin, 1999) reported that after intraperitoneal administration of
curcumin at a dose of 0.1 g/kg body weight to mice, the levels of curcumin in the plasma,
liver, intestines, kidneys, spleen and brain were 2.25, 26.90, 177.04, 7.51, 26.06 and 0.41μg/g,
respectively. Marczylo et al. (Marczylo et al., 2007) also showed poor bioavailability of
curcumin. They found that the maximum serum concentration of curcumin, curcumin sulfate
and curcumin glucuronide were 6.5±4.5 nM, 225±0.6 nM and 7.0±11.5 nM, respectively
after oral dosing of 340 mg/kg curcumin to rats. In a clinical trial of curcumin treatment for
patients with colorectal cancer, neither curcumin nor its metabolites were detected in blood or
urine with an oral dose of 440~2200 mg/day curcumin extract at up to 29 days of daily
treatment, but curcumin and curcumin sulfate were found in feces (Sharma et al., n.d.).
Similarity, human studies also show that curcumin has poor bioavailability. In a human Phase
II clinical trial, only 22~41 ng/mL curcumin was detected in the plasma of patients with
pancreatic cancer who had received 8 g/day of curcumin by mouth (Dhillon et al., 2008).
More recently, Hiroki et al. (Sasaki et al., 2011) found that after an oral dose of 30 mg/kg
curcumin powder, maximum curcumin concentration in plasma was 1.8 ng/mL after 6 h of
dosing.
The poor solubility in water, instability at physiological pH and low oral bioavailability hinder
its industrial use. However, curcumin may be encapsulated by a number of efficient
encapsulation techniques, which include nanoemulsions, to improve its water solubility,
stability and bioavailability.
3. Methods of preparation of curcumin-loaded nanoemulsions
Nanoemulsions are biphasic dispersion of two immiscible phases with one dispersed in the
other: either water in oil (W/O) or oil in water (O/W) droplets stabilized by an amphiphilic
8
surfactant (Y. Singh et al., 2017). Typically, nanoemulsions are defined with a very small
droplet size (r < 100 nm) (Salvia-Trujillo, Martín-Belloso, & McClements, 2016), and
because they are nonequilibrium systems, their formation requires energy. The generation of
nanoemulsions can be achieved through two essentially different approaches: (i) low-energy
and (ii) high-energy methods (Y. Yang, Marshall-Breton, Leser, Sher, & McClements, 2012).
Low-energy emulsification makes use of internal chemical energy of the system, which
allows to produce small droplets without or with a gentle stirring (Ren et al., 2019). In
contrast, high-energy production methods rely on mechanical devices (e.g. microfluidizer,
high-pressure homogenizer, etc.) to produce intense disruptive forces that break up particles
into smaller sizes (Ren et al., 2019; Y. Yang et al., 2012). These low energy emulsification
methods have gained more attention in recent years due to lower operational costs and
equipment investments compared with high energy methods (Borrin, Georges, Moraes, &
Pinho, 2016). Moreover, they may be less detrimental to heat sensitive bioactive compounds.
3.1. Low-energy emulsification methods
Low-energy methods include many different methods, such as phase inversion and
self-emulsification. The phase inversion methods often involve the inversion of the surfactant
curvature from positive to negative or negative to positive (Calderó et al., 2016; Solans &
Solé, 2012). This can be achieved through two different routes: changing the temperature
while keeping the constant composition (Phase Inversion Temperature, PIT), and changing the
composition while keeping the constant temperature (Phase Inversion Composition, PIC)
(Calderó et al., 2016; Ren et al., 2019).
3.1.1. Phase inversion temperature method
The PIT method is based on a phase transition by the change in the nonionic surfactant
spontaneous curvature induced by temperature. At low temperatures, the
temperature-sensitive surfactants are hydrophilic and have a positive spontaneous curvature.
9
In contrast, the surfactants are more hydrophobic and the spontaneous curvature tends to
become negative with increasing temperatures. At intermediate temperatures
(hydrophilic-lipophilic balance -temperature), the hydrophilic and lipophilic properties of
surfactants are balanced, and the mean spontaneous curvature is close to zero (Ren et al., 2019;
Sharif, Astaraki, Azar, Khorrami, & Moradi, 2012). The affinity of the surfactant for the
aqueous and oil phases is exchanged by varying temperature, causing a change in phase from
water-in-oil (W/O) to oil-in-water (O/W) (Boscán, Barandiaran, & Paulis, 2018). A schematic
representation of the PIT method to form O/W nanoemulsions can be observed
in Fig. 2a. First an O/W emulsion is prepared by mixing of all components (surfactant,
cosurfactant, oil and water, etc.) at room temperature, then gently heating the system to above
or around the PIT temperature followed by rapidly cooling down to spontaneously form fine
oil droplets. The PIT temperature, is defined as the temperature where the mixed system has a
low turbidity due to the formation of a bicontinuous emulsion (Chuesiang et al., 2019). It is
commonly determined by measuring the electrical conductivity, since there is a drastic
difference between the electrical conductivity values of the oil phase and water phase (de
Oliveira Honse et al., 2018). pH is another property that can be used to evaluate the PIT
temperature. In general, at the temperature above the PIT, the pH of the system is unstable and
can not be measured. However, the pH is always stable while below the PIT (Mashhadi,
Javadian, Tyagi, Agarwal, & Gupta, 2016).
Recently, several groups have reported the formation of curcumin-loaded nanoemulsions by
PIT method (Table1). Jintapattanakit et al. (Jintapattanakit, Hasan, & Junyaprasert, 2018)
prepared curcuminoid-loaded nanoemulsions with a nonionic surfactant, polyethylene
glycol-40 hydrogenated castor oil (RH40) through the PIT method. The effect of curcuminoid
and RH40 concentrations on the particle size, zeta potential and stability was investigated in
detail. The results show that the PIT method may be more efficient than other methods for the
10
production of edible nanoemulsions using RH40 as the surfactant. Calligaris et al. (Calligaris
et al., 2017) also obtained curcumin-loaded nanoemulsions by the PIT method. They
demonstrated that the maximum lipid content allowing curcumin loaded transparent
microemulsions was greatly affected by the oil type and physical state of lipid. This study
contributes to the design and formation of curcumin-loaded nanoemulsions, while giving an
interesting approach for the delivery of lipophilic compounds.
3.1.2. Phase inversion composition method
The PIC method is based on changing the water/oil ratio of the system through progressively
adding one of the components (water or oil) over a mixture of the other components at a
constant temperature during the procedure to obtain nanoemulsions (Solans & Solé, 2012).
The preparation of O/W nanoemulsions by the PIC method can be divided into two steps:
(i) mixing of the organic phase (oil + surfactant) to obtain a fixed composition and (ii) adding
water resulting in the formation of O/W nanoemulsions (Fig. 2b). The mechanism is similar to
the temperature-induced curvature change in the PIT method. Water addition leads to a
progressively increase in the hydration grade of the surfactant, and the spontaneous curvature
of surfactant changes from negative to positive (Roger, 2016).
Maestro et al. (Maestro, Solè, González, Solans, & Gutiérrez, 2008) developed nanoemulsions
of oleylamine using oleylammonium as surfactant by the PIC method. The formation of
nanoemulsion was studied in an ionic system instead of previous cationic systems. The
method has been intensively investigated for nanoemulsions preparation (Solè et al., 2010; H.
J. Yang, Cho, & Park, 2009; Yu, Li, Xu, Hao, & Sun, 2012). Nevertheless, no report can be
found in the literature related to fabrication of curcumin-loaded nanoemulsion using PIC
method. The operation steps of PIC method are quite straightforward, and the technique is
easy to be scaled. Therefore, it could be a promising method for producing curcumin-loaded
nanoemulsions.
11
3.2. High-energy emulsification methods
In recent decades, high-energy methods have been the most studied processes. A variety of
high-energy methods have been proposed in the literature for preparing emulsions, including
high pressure homogenization (HPH), microfluidization and ultrasonication. Compare with
low-energy approaches, high-energy methods are often more effective at producing small
droplet sizes as nanoemulsions are generated using mechanical devices with intensive
disruptive forces, and they can use various types of oils and emulsifiers. Promising
formulations for curcumin nanoemulsions have been formulated with high energy methods.
3.2.1. Ultrasonication
Ultrasonication is an effective method for reducing the emulsion mean droplet diameter. In
ultrasound emulsification, the energy is supplied by a sonotrode (sonicator probe) containing
a piezoelectric quartz crystal (Jafari, Assadpoor, He, & Bhandari, 2008). The tip of the
sonicator probe must be placed in the center of the premix emulsion, at a certain immersion
depth in the sample (Fig. 3a). The ultrasound treatments are performed for different times at
different frequencies and different powers, and the temperature is controlled using a cold
water bath that dissipates the heat generated during the process. During ultrasonication,
micro-bubbles are contracted and expanded due to ultrasonic waves throughout the liquid
medium generating compressive and tensile stresses. The formation and collapse of these
bubble (vapor cavities) in a flowing liquid result in cavitation, thereby rupturing the dispersed
droplets (Modarres-Gheisari, Gavagsaz-Ghoachani, Malaki, Safarpour, & Zandi, 2019).
This technique has been used by several authors to generate curcumin-loaded nanoemulsions
(Table1). In the study of Páez-Hernández et al. (Páez-Hernández, Mondragón-Cortez, &
Espinosa-Andrews, 2019), the effects of processing parameters (power, amplitude and
treatment time) and formulation parameters (diverse types of oil and oil volume fraction) were
evaluated to produce curcumin-loaded nanoemulsions using hydroxylated lecithin as the
12
emulsifier agent. The increase of time, amplitude, power and oil volume fraction caused
decrease of mean droplet size and polydispersity index. The mean droplet sizes of the
curcumin-MCT emulsion were significantly lower than the curcumin-grapeseed and
curcumin-olive emulsions. Nevertheless, the zeta potential of the emulsions had similar values
independent of the processing parameters used. Abbas et al. (Abbas, Bashari, Akhtar, Li, &
Zhang, 2014) developed food-grade curcumin-loaded nanoemulsions stabilized by modified
starches by ultrasonication. In their work, impacts of major emulsification process variables
and formulation parameters on the mean droplet diameter, polydispersity index and charge on
the emulsion droplets were investigated. In another work, Sari et al. (Sari et al., 2015)
prepared curcumin-MCT nanoemulsions via ultrasonication using whey protein concentrate
70 and Tween 80 as emulsifiers. The encapsulation efficiency of curcumin in the
nanoemulsions reached 90.56 ± 0.47%. The curcumin-loaded nanoemulsions showed a good
stability and improved bioaccessibility. These studies indicated that the ultrasound-assisted
emulsification could be successfully used for the preparation of curcumin-loaded
nanoemulsions. However, drawbacks of ultrasonication are related to the low volumes that
can be prepared, and the difficulty of scaling-up.
3.2.2. High pressure homogenization
HPH is a widely used technique to produce stable O/W emulsions with fine texture. In the
process, a high pressure pump (regularly up to 100 MPa) is used to pass the fluid through a
narrow gap of a valve (Fig. 3b). Fluids are subjected to a wide range of forces, such as intense
shear, cavitation, turbulent flow and temperature, resulting in disruption of droplets
(Modarres-Gheisari et al., 2019). In most emulsion productions, HPH can be divided in two
steps: (i) converting oil and water phases into a coarse emulsion; and (ii) preparing the final
fine emulsion through high-pressure systems (Peng et al., 2015).
Many studies have investigated nanoencapsulation of curcumin by HPH (Table1). For
13
example, Mistry et al. (Mistry, Mohapatra, & Dash, 2012) prepared a curcumin delivery
system via HPH using two different emsulsifiers (polyvinyl alcohol (PVA) and poloxamer
407). They investigated the impacts of the HPH process and emulsifiers on the
physicochemical properties of glycerol monooleate (GMO)/chitosan nanoemulsions. The
particle size of the nanoemulsion was reduced to 50–65% after three cycles of HPH. It was
concluded that HPH effectively reduced the particle size of the GMO/chitosan nanoemulsions
loaded with curcumin. Similarly, Ma et al. (Ma et al., 2017) encapsulated curcumin using
HPH in three various oil phases (i.e. MCT, canola oil and linseed oil) and three different
emsulsifiers (i.e. Tween-80, lecithin, whey protein isolation and acacia). They revealed
correlation between emsulsifier type, oil phase and physicochemical properties (curcumin
content, particle size, potential, physical stability and storage stability) of curcumin
formulations. Curcumin-MCT nanoemulsions achieved the maximum curcumin content
compare to other oils. The increase of oil phase concentration led to increase curcumin
content, particle size and viscosity of the emulsions but decrease stability. However, oil type
and concentration have no significant effect on zeta-potential of curcumin nanoemulsions. In
a recent work by Silva et al. (Silva et al., 2019), O/W nanoemulsions for encapsulation of
curcumin were obtained by HPH using whey protein isolate as surfactant with MCT as lipid
phase. Multilayer nanoemulsions were then formed by the deposition of a chitosan layer onto
curcumin nanoemulsions. Both nanosystems (nanoemulsions and multilayer nanoemulsions)
showed a considerable stability under storage conditions and at stomach pH conditions.
Moreover, the curcumin-loaded nanosystems exhibited enhanced antioxidant activity and
increased bioaccessibility compared to the free curcumin. Therefore, HPH can be used to
create curcumin-loaded nanoemulsions and so improve the properties of curcumin.
3.2.3. Microfluidization
Microfluidization is one of the most efficient method of producing nanoemulsions with small
14
droplets. Conventional microfluidizers typically use a two-steps procedure to produce
nanoemulsions: (i) forming the initial coarse emulsion by blending the oil and water phases;
and (ii) producing the final fine emulsion by passing coarse emulsion through the
microfludizer (Bai, Huan, Gu, & McClements, 2016; Bai & McClements, 2016). The coarse
emulsion enters the homogenizer using a high pressure pumping device, then it is divided into
two streams that flow through narrow channels to impinge on each other at high velocities,
thereby producing extremely intense disruptive forces (turbulence, stresses, shear and
cavitation) that lead to generation of fine emulsion (Bai et al., 2016) (Fig. 3c). In addition, a
one-step dual channel microfluidization method was also used to fabricate nanoemulsions.
The oil and aqueous phases were separately fed into the microfluidizer from two inlet
reservoirs, then they flew through the homogenizer (Bai & McClements, 2016) (Fig. 3d).
Recently, there have been many studies applying microfluidization to produce stable
curcumin-loaded nanoemulsions (Table1). In a study conducted by Raviadaran et
al.(Raviadaran, Chandran, Shin, & Manickam, 2018), stable palm oil-based O/W
nanoemulsions loading curcumin were successfully formulated using a microfluidizer. A
response surface methodology with three independent factors (pressure, number of cycles and
surfactant concentration (Tween 80)) was carried out to determine the optimum conditions for
the droplet size based on the single-factor experimental results. The mean droplet size
decreased with increased surfactant concentration and operating pressure. More cycles were
needed to achieve smaller droplet size at lower operating pressure. However, when droplet
size reached its minimum values, the number of cycles had no significant effects. In this study,
the microfluidizer generated nanoemulsions with droplet size ranging 200 nm–300 nm at
operating pressure of 350 bar and beyond 5 cycles. Also, Páez-Hernández et al.
(Páez-Hernández et al., 2019) formulated curcumin-loaded nanoemulsions via
microfluidization using different formulations and process parameters to evaluate their effect
15
on droplet size, zeta-potential, and polydispersity of the emulsions. The impact of operating
pressure and number of cycles on particle size was similar to the results observed by
Raviadaran et al.(Raviadaran et al., 2018) as mentioned previously. Based on these results, the
optimal curcumin emulsion produced by microfluidization had a nanometric size, high
negative zeta potential and low polydisperity value. In another study, Artiga-Artigas et al.
(Artiga-Artigas, Lanjari-Pérez, & Martín-Belloso, 2018) prepared nanoemulsions containing
curcumin through microfluidization using different surfactants. The curcumin-loaded
nanoemulsions produced had a suitable physiochemical characteristics regarding particle size
(≤400 nm), zata potential (≤-37mv) and encapsulation efficiency (≥75%). Moreover, the
curcumin -encapsulated emulsion showed a good antioxidant capacity. Hence,
microfluidization can be suggested as a suitable technology to produce curcumin
nanoemulsions.
3.2.4. Membrane emulsification
Membrane emulsification is a promising technique to produce emulsions with a small size and
a narrow droplet size distribution. It is a more recent process that also uses mechanical forces
but with lower energy input compared to other emulsification methods (Alliod, Messager,
Fessi, Dupin, & Charcosset, 2019; Arkoumanis, Norton, & Spyropoulos, 2019). The low
energy requirement leads to low temperature increase during the process of emulsification
which gives better stability to temperature sensitive substances (Alliod et al., 2018). Mainly,
two types of membrane emulsification process have been developed: direct membrane
emulsification (DME) and premix membrane emulsification (PME). In DME, the dispersed
phase is passed through a microporous membrane into an agitating or cross-flowing
continuous phase to produce small size nanodroplets. In PME, droplets are formed by
introducing the prepared coarse emulsion (premix) through a porous membrane. A schematic
representation of DME and PME to form O/W nanoemulsions is shown in Fig. 3e and Fig. 3f.
16
PME has several advantages compared to DME (Alliod et al., 2018; Santos, Vladisavljević,
Holdich, Dragosavac, & Muñoz, 2015): (i) the mean droplet size is smaller than in DME; (ii)
the dispersed phase flux is higher than in DME; (iii) the process parameters are easier to
control than in DME.
For the formation of nanoemulsions, membrane emulsifications are particularly attractive,
especially PME. In PME, the droplet size is affected by membrane properties (e.g., pore size,
thickness, tortuosity, porosity and hydrophilicity/hydrophobicity), process parameters (e.g.,
transmembrane pressure and rotational velocity), formulation characteristics (surfactant type
and concentration, dispersed phase volume fraction, emulsion viscosity) (Arkoumanis et al.,
2019; Nazir, Schroën, & Boom, 2013). Servel studies have investigated the impact of these
factors (Table1). For instance, Alliod et al. (Alliod et al., 2019) prepared O/W and W/O
nanoemulsions by extruding a coarse emulsion through Shirasu Porous Glass (SPG)
membranes with a mean pore diameter of 0.5 µm, and investigated the effect of viscosities
(continuous phase viscosity, dispersed phase viscosity as well as dispersed phase content) on
the membrane pressure and droplet size. The dispersed phase viscosity had a lower impact on
the membrane pressure, and no significant influence on the droplet size; the continuous phase
viscosity and the emulsion viscosity both had a significant impact on the membrane pressure
and mean droplet size (the pressure through the membrane increased with the continuous
phase viscosity and dispersed phase content, and the mean droplet size decreased with
increased continuous phase viscosity and dispersed phase content). In another work by Alliod
et al. (Alliod et al., 2018), the effect of process parameters (cycle number, membrane pore
size, flowrate) on droplet size of O/W emulsion was investigated. In this study, only one cycle
was sufficient to produce droplets with small size. The mean droplet size decreased with
decreasing membrane pore size. Thus, the droplet size can be controlled by changing the pore
size. Regarding membrane length, the shortest membrane led to smaller droplets as it required
17
higher pressure than the longer membrane. The droplet size decreased with increasing
flowrate. This may be due to the higher wall shear stress applied at higher flowrate. Several
other studies have shown that nanoemulsions prepared by PME had good physicochemical
characteristics (droplet size, narrow size distribution, encapsulation efficiency) and exhibited a
considerable stability (Berendsen, Güell, & Ferrando, 2015; Gehrmann & Bunjes, 2016, 2017;
Joseph & Bunjes, 2012). To the best of our knowledge, there are no studies reporting the
formulation of curcumin-loaded nanoemulsions by PME method.
4. Stability and bioaccessibility of curcumin-loaded nanoemulsions
4.1. Chemical stability of curcumin-loaded nanoemulsions
In nanoemulsion delivery systems, curcumin molecules are typically located within the
hydrophobic interior of the oil droplets, but some of them may also be located close to the
oil–water interface due to the polar groups on the curcumin. In this case, curcumin is
protected from active substances within the aqueous phase that would typically promote its
chemical degradation (Sanidad et al., 2019). Therefore, the chemical stability of curcumin is
enhanced by encapsulating it in nanoemulsions. Some effects of nanoemulsions on stability of
curcumin have been presented in Table 2.
Zheng et al. (Zheng, Zhang, Chen, Luo, & McClements, 2017) assessed the impact of
different delivery system (aqueous dimethyl solutions, O/W nanoemulsions, and filled
hydrogel beads) on the chemical stability of curcumin under both acidic and neutral
conditions. After 14 days of storage at 55 °C, the yellowness (b* value) of the curcumin
emulsion decreased to 33% of its original value at pH 3 and to 93% of its original value at pH
7, while the yellowness of the curcumin solutions decreased to 17% of its original value at pH
3 and to 73% of its original value at pH 7. In this study, the changes of yellow color intensity
indicated that curcumin degradation occurred. Xu et al. (Xu, Wang, & Yao, 2017) observed
that about 25% of curcumin degraded after 40 days storage at 37 °C in the dark for curcumin
18
nanoemulsions prepared with casein and soybean soluble polysaccharide complex. However,
the curcumin degradation in curcumin solutions was about 94% after 2 days of storage at
37 °C in the dark. Curcumin storage stability in nanoemulsions was significant better than in
solutions confirming that nanoemulsions are an efficient system to protect curcumin from
chemical degradation by avoiding the interaction between curcumin molecules and other
reactive substances within solutions.
The composition and structure of delivery systems significantly affect curcumin stability.
Various studies have revealed that the stability of curcumin is influenced by the nature and
concentration of emulsifier. Kharat et al. (Kharat, Zhang, & McClements, 2018) evaluated the
impact of emulsifier type (sodium caseinate, Tween 80, quillaja saponin, gum arabic) and
concentration (critical and excess) on the stability of curcumin-loaded nanoemulsions. They
observed that the degradation of curcumin in saponins-stabilized nanoemulsions was
relatively rapid after 15 days of storage due to the fact that saponins containing conjugated
double bonds generated free radicals that promote peroxidation reactions, while the other
three emulsifiers behave fairly similarly. The authors also reported that the emulsifier level in
the emulsions did not significantly affect the curcumin degradation since most of the excess
emulsifier was remained in the aqueous phase. Similarly, Artiga-Artigas et al. (Artiga-Artigas
et al., 2018) assessed the impact of three molecularly different surfactants: lecithin, Tween 20
and sucrose monopamitate, and their concentration on the stability of curcumin-loaded
nanoemulsions, and evaluated their antioxidant capacity. They found that the stability of
curcumin in nanoemulsions was not significantly correlated to the concentration of surfactant.
They also observed that curcumin loaded nanoemulsions with a concentration of lecithin over
1% showed long-term stability and exhibited higher antioxidant capacity than two other
surfactants due to the fact that lecithin contains phosphate ions that are able to form hydrogen
bonds with phenolic hydroxyls of curcumin, preventing its autoxidation and hence,
19
maintaining the antioxidant capacity of curcumin. However, in nanoemulsions containing
either Tween 20 or sucrose monopalmitate, antioxidant capacity was negatively correlated to
the encapsulation efficiency due to the fact that curcumin was not really encapsulated within
the oil phase but retained in the surfactant by hydrogen bonding after nanoemulsions
destabilization. Therefore, curcumin exposed to the aqueous media may undergo a
spontaneous auto-oxidation degradation and loss of antioxidant capacity.
4.2. Bioaccessibility of curcumin-loaded nanoemulsions
In vitro simulated digestion systems are commonly used to evaluate the bioaccessibility of
curcumin encapsulated within emulsion-based delivery systems (Ahmed, Li, McClements, &
Xiao, 2012; H. R. Park et al., 2019; Silva et al., 2019). The in vitro digestion model consists
of three consecutive steps: oral, gastric, and small intestinal phase. To mimic digestion,
simulated saliva fluid (SSF) is obtained from mucin and α-amylase at around neutral pH
values (e.g. 6.8) for a fixed period of time (e.g.10 min) at a body temperature of 37 °C.
Simulated gastric fluid (SGF) involves the addition of salts (e.g. NaCl, KCl, CaCl2, NaHCO3),
acids (e.g. HCl) and digestive enzymes (e.g. pepsin) at an acidic pH value (e.g. 1.2–4) for a
fixed period of time (e.g. 2 h) at 37 °C. Simulated intestinal fluids (SIF) involve the addition
of bile extract, pancreatin and electrolyte solution (e.g. NaCl, KCl, CaCl2) at a neutral to
alkaline pH values (e.g. 6.5-7.5) for a fixed period of time (e.g.2 h) at 37 °C (H. R. Park et al.,
2019; Sarkar, Goh, Singh, & Singh, 2009). In vitro lipid digestion assays have been developed
to quantify the release of curcumin (Aditya et al., 2015; Ahmed et al., 2012; H. R. Park et al.,
2019; Sari et al., 2015). Lipid digestion products (e.g., free fatty acids) generated by lipolysis
of the oil can form various colloid phases (e.g., mixed micelles) that are available to solubilize
the released curcumin. The fraction of curcumin release into the mixed micelle phase after
lipid digestion can be used to quantify its bioaccessibility (Ahmed et al., 2012). Many studies
considering the bioaccessibility of curcumin-loaded nanoemulsions are discussed in the
20
following section and have been summarized in Table 2.
Many studies show that emulsion-based systems can greatly increase the bioavailability of
curcumin within the GIT compared to crystalline curcumin dispersed within water. Aditya et
al. (Aditya et al., 2015) encapsulated curcumin and catechin in a water-in-oil-in-water
(W/O/W) double emulsion using two-steps emulsification. They reported that encapsulation
of curcumin within an emulsion-based system enhanced 4-fold their bioaccessibility (72%)
compared to that of freely suspended curcumin (16%), because the presence of mixed
micelles available to incorporate curcumin. In a recent work, Park et al. (S. J. Park, Garcia,
Shin, & Kim, 2018) prepared Tween 80 - stabilized nanoemulsions and curcuminoids-loaded
nanoemulsions developed by combining a liquid lipid (MCT) and solid lipid (glycerol
monostearate, GMS). The encapsulated curcumin exhibited a notable increase in
bioaccessibility (75±1.24%) compared with curcumin solution (1.7±0.24%). In another work,
Zheng et al. (Zheng, Peng, Zhang, & McClements, 2018) prepared curcumin-loaded
nanoemulsions using three different methods: the conventional oil-loading method, the
heat-driven method, and the pH-driven method. The different curcumin formulations were
then subjected to a simulated GIT model consisting of mouth, stomach, and small intestine
phases. All three nanoemulsions had fairly similar curcumin bioaccessibility values (74−79%),
significantly higher than that of curcumin solution (10%). It suggests that encapsulating
curcumin within small lipid particles may be advantageous for improving its absorption from
the GIT. Furthermore, bioaccessibility of curcumin in emulsion-based systems is influenced
by many factors, including oil composition, droplet size and curcumin-emulsifier interactions.
Several researches indicated that the bioaccessibility of curcumin is affected by the type and
the amount of carrier oil present in the nanoemulsion- based delivery systems. The nature and
physicochemical properties of the free fatty acid, generated by digestion of the oil, are quite
different (Ye, Cao, Liu, Cao, & Li, 2018). Long chain fatty acids form mixed micelles more
21
easily than medium chain fatty acids, and short chain fatty acids produced by lipolysis of the
SCT can not form mixed micelles to solubilize and transport curcumin. The mixed micelles
formed by long chain fatty acids have a better solubilization capacity because of the large
dimensions of the hydrophobic core. Ahmed et al. (Ahmed et al., 2012) examined the
influence of triacylglycerol molecular weight on curcumin bioaccessibility. Emulsions
containing only short chain triacylglycerols (SCT) within the carrier lipid had only about 1%
bioaccessibility. However, utilization of MCT and long chain triacylglycerols (LCT) within
the emulsion can greatly increase curcumin bioaccessibility due to the presence of mixed
micelles. The bioaccessibility of curcumin was ∼40% in the LCT nanoemulsions but ∼20%
in the MCT nanoemulsions when the concentration of oil in the nanoemulsion was lower than
1.5%. Similarly, Shah et al. (Shah, Zhang, Li, & Li, 2016) observed that there were
differences in curcumin bioaccessibility between MCT and LCT nanoemulsions when the oil
was almost fully digested. In their study, the bioaccessibility was around 32% in the MCT
nanoemulsions but around 65% in the LCT nanoemulsions. The bioaccessibility of curcumin
may increase with increasing total lipid content, due to the increase in mixed micelles
available to solubilize the curcumin. However, the bioaccessibility may not increase when the
amount of lipid is higher than a certain content due to the fact that the lipid phase is not fully
digest, which results in an incomplete release of curcumin from the droplets into the mixed
micelles phase. For example, Ahmed et al. (Ahmed et al., 2012) prepared an O/W
nanoemulsion stabilized by 1 wt.% protein. The bioaccessibility of curcumin increased as the
total lipid content increased, while the bioaccessibility of curcumin was similar at 1.5 and
2.0 wt. % lipid when using LCT as the carrier lipid.
Various studies have revealed that the bioaccessibility of curcumin was dependent on the
emulsifier type. Emulsifier type has an influence on the curcumin bioaccessibility, by altering
the droplet surface area within the digestive tract, or by changing the ability of digestive
22
enzymes to bind onto the emulsions droplet surface. During the simulated digestion,
nanoemulsions show an increase in size due to the addition of digestive enzymes and the
change of pH, ionic strength or shear (aggregation, coalescence and flocculation of the oil
droplets), leading to a decreased surface area for enzyme interaction (Golding et al., 2011;
Hur, Decker, & McClements, 2009). Nanoemulsions stabilized by non-ionic emulsifier are
more stable in acidic gastric environments owing to steric repulsions provided by the
polyoxyethylene head groups resulting in a slowly increase in the droplets size with a large
surface area for the binding of bile salts and lipase (Golding et al., 2011; Pinheiro et al., 2013).
For example, Pinheiro et al. (Pinheiro et al., 2013) reported that higher curcumin
bioaccessibility during digestion (initial , stomach, duodenum, jejunum, ileum) for
nanoemulsions stabilized by Tween 20 (non-ionic, ∼16.0% in ileum), as compared to the ones
stabilized by dodecyltrimethylammonium bromide (DTAB, cationic, ∼1.0% in ileum). The
increased bioaccessibility for Tween 20-stabilized nanoemulsions was attributed to the
smaller increase in emulsion size (∼350 nm) when compared with that of the size of
DTAB-stabilized nanoemulsions (∼900 nm) during the digestion process. In addition, it has
been suggested that the interaction promoted by the strong electrostatic binding between
cationic emulsifier and bile salts resulted in the binding of lipase and thus free fatty acid
release (Pinheiro et al., 2013). However, with the anionic emulsifier-stabilized emulsion,
charged repulsion between anionic emulsifier and anionic components (e.g. bile salts) or free
fatty acid could inhibit effective binding of bile salts and thus prevent the binding of lipase
(Pinheiro et al., 2013).
Several researches have shown that emulsifier-curcumin interactions can reduce the curcumin
bioaccessibility as part of curcumin is not detected in the micelle phase. Pinheiro et al.
(Pinheiro, Coimbra, & Vicente, 2016) found that total curcumin bioaccessibility in lactoferrin
and lactoferrin/alginate-stabilized nanoemulsions were relatively low (∼5%) in jejunum and
23
ileum. In their work, lactoferrin was responsible for the low bioavailability of curcumin in
simulated digestion system. Silva et al. (Silva et al., 2018) observed that lower
bioaccessibility values were observed for polyelectrolytes (0.04% chitosan 1st, 0.04% alginate
2nd
and 0.02% chitosan 3rd
layer) multilayer nanoemulsions (26.98 ± 3.99%) when compared
nanoemulsions (43.64 ± 6.36%). These results may be explained by the fact that
polyelectrolyte layers were efficient in protecting the release of curcumin from the multilayer
nanoemulsions, leading to undigested nanosystems able to retain curcumin.
5. Applications of curcumin-loaded nanoemulsions
Curcumin has attracted growing consideration owing to its wide range of beneficial biological
and pharmacological activities, such as antioxidant, anti-inflammatory and anticancer
activities (Almeida, Sampaio, Bastos, & Villavicencio, 2018; Ghasemi et al., 2019; Güran,
Şanlıtürk, Kerküklü, Altundağ, & Süha Yalçın, 2019), but its hydrophobic nature limits its
utilization as a nutraceutical in many applications (Huang et al., 2016). Hence, research has
been conducted to encapsulate curcumin using delivery systems that can solve these
limitations. Compared to curcumin alone, encapsulated curcumin has shown greater biological
activity as the delivery system provides sustained release, good stability and enhanced
curcumin solubility in aqueous medium (Hashim et al., 2019; Mohammadian, Salami, Momen,
Alavi, & Emam-Djomeh, 2019; Sorasitthiyanukarn, Muangnoi, Thaweesest, Rojsitthisak, &
Rojsitthisak, 2019).
5.1. Antioxidant activity of curcumin nanoemulsions
Curcumin has been reported to exhibit various antioxidative effects in many cellular and
animal models of different diseases (Eybl et al., 2006; Phan et al., 2001). Generally, it exerts
an antioxidant activity in a direct or an indirect way by scavenging oxygen free radicals and
inducing an antioxidant response, respectively (Antunes, Araújo, Darin, & Bianchi, 2000). In
fact, various reports have indicated that curcumin may be a beneficial antioxidative agent, but
24
its chemistry properties limit its potential as a therapeutic agent in clinical trials. Therefore,
researchers focused their attention on the feasibility of using nanotechnology-based systems,
such as nanoemulsions, as efficient carriers of curcumin.
Table 3 summarizes some of the recent studies on antioxidant effects of curcumin-loaded
nanoemulsions. For instance, Sari et al. (Sari et al., 2015) successfully formulated
curcumin-loaded nanoemulsions by ultrasonification using whey protein concentrate-70 and
Tween-80 as emulsifiers. The encapsulated curcumin showed a slightly lower DPPH radical
scavenging activity as compared to that of unencapsulated curcumin, but the encapsulation
not only preserves the antioxidant activity but also increases curcumin stability. In other
words, the antioxidant activity of encapsulated curcumin is bio-accessible, i.e., released from
the food matrix and solubilized. In another study, Chuacharoen et al. (Chuacharoen & Sabliov,
2019) fabricated three various types of curcumin-nanocarriers including nanosuspensions,
nanoparticles and nanoemulsions using lecithin along with Tween 80 as surfactants and MCT
as oil phase in nanoemulsions. Curcumin-nanocarriers were added into milk for evaluation of
the lipid oxidation and color changes during storage. Antioxidant activity was determined by
TABRS (thiobarbituric acid reactive substances) assay, and color of milk was determined by
spectrophotometer. The results show that all curcumin-nanocarriers had the capability to
inhibit lipid oxidation, which enhanced nutritional quality of milk. On the other hand,
nanocurcumin-fortified milk had color changes insignificant from control milk after 5 days.
Similarity, Joung et al. (Joung et al., 2016) observed significantly reduced lipid oxidation of
milk during storage when using a curcumin-nanoemulsions-fortified milk as compared to
control milk and milk containing empty nanoemulsions (without curcumin). These results
suggested that curcumin-nanoemulsions have potential applications in the beverage industry
because of their antioxidant properties.
5.2. Anti-inflammation activity of curcumin nanoemulsions
25
Curcumin has been used traditionally as an anti-inflammatory agent. It suppresses the
activation of free radical-activated transcription factors, such as nuclear factor κB (NF-κB)
and activator protein-1 (AP-1), and reduces the generation of pro-inflammatory cytokines
such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (Chen et al., 2017;
Rakariyatham et al., 2019). However, the therapeutic outcome of clinical studies has remained
challenging due to its hydrophobic nature. In order to achieve optimum therapeutic effect,
nanoemulsions have been proposed as a suitable delivery system in the treatment of
inflammation and infections due to their ability to prolong the retention time of curcumin and
enable control over the release of incorporated curcumin.
A number of publications have dealt with curcumin nanoemulsions formulations for
anti-inflammatory applications. Some effects of curcumin-loaded nanoemulsions on
anti-inflammation activity of curcumin are presented in Table 3. For example, Wang et al.
(Wang et al., 2008) assessed the anti-inflammation activity comparing the inhibition effect on
the edema of mouse ear (12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema of
mouse ears) between curcumin encapsulated in Tween 20-stabilized MCT-carried
nanoemulsions and curcumin solution (10% Tween 20 water solution). The oral
administration of 1% curcumin solution showed little inhibition effect on TPA-induced edema
of mouse ear as Tween 20 could not prevent the fast metabolism of curcumin in mouse body.
On the contrary, it was found that 1% curcumin-loaded nanoemulsions had significant
inhibition effect on TPA-induced edema of mouse ear (43%~85% reduction) due to the fact
that nanoemulsions promoted the absorption of curcumin within the intestine tract. The result
suggested that curcumin in nanoemulsions significantly improved the anti-inflammation
activity of curcumin. Also, Thomas et al. (Thomas et al., 2017) reported that five different
curcumin nanoemulsions with the same quantity of curcumin, stabilized by different radios of
Tween 80 and polyethylene glycol (PEG 400), showed a good ex-vivo skin permeation
26
(75.306±5.4~107.1±5.9 µg/cm3/h for flux values) and skin deposition (17.46%~46.07%). In
addition, nanoemulsions gels were developed by incorporation of the optimized formulation
nanoemulsions (oil: surfactant: distilled water=15:40:45, Labrafac PG: Triacetin=1:1, Tween
80: PEG=2:1) into 2% chitosan at acidic pH conditions. The formulated gel had a good
spreadability because of sufficient viscosity (504±21.4 cps) and compatibility to human skin
due to neutral pH (6.4±0.121). Moreover, 98% of the formulated gel reached the skin. The
nanoemulsions gel had a lower flux (68.88 μg/cm3/h) compared to the corresponding
nanoemulsions (76.05 μg/cm3/h), but it had higher amount of curcumin (980.75±88 μg)
retained in the skin compared to the corresponding nanoemulsions (771.25±67 μg).
Furthermore, incision wound model rats treated with the nanoemulsions gel showed full
wound closure after 12-days treatment whereas the control groups dragged behind
significantly. These studies have proved that curcumin-loaded nanoemulsions can be used for
improving wound healing as they enhance the bio-accessible anti-inflammation activity of
curcumin and possess antioxidant activity to prevent oxidative damage in vivo.
5.3. Anti-cancer activity of curcumin nanoemulsions
Anti-cancer activity of curcumin has been extensively investigated on numerous kinds of
malignancies, such as breast, prostate, pancreatic and gastric cancers (Liu & Ho, 2018; Teiten,
Gaascht, Eifes, Dicato, & Diederich, 2010; Bimonte et al., 2016; Jakubek et al., 2019).
Curcumin inhibits transformation, proliferation, suppresses tumors metastasis and induces
apoptosis through the regulation of various molecular targets (transcription and growth factors)
and its receptors (inflammatory cytokines, protein kinases and other enzymes) (Guan et al.,
2017; Rodrigues, Anil Kumar, & Thakur, 2019). However, pharmaceutical significance and
therapeutic efficacy of curcumin is limited due to its poor pharmacokinetic properties (poor
bioavailability and short biological half-life). To overcome pharmaceutical issues, various
27
strategies have been employed for effective delivery of curcumin which include
nanotechnology-based approaches. Nanoencapsulation based nanoemulsions have the ability
to increase the efficacy of curcumin pharmaceutical significance.
Various in vitro and in vivo studies obviously reveal that nanoemulsions can enhance the
anticancer efficacy of curcumin. Some studies on application of curcumin nanoemulsions in
cancer therapy are illustrated in Table 3. For example, Machado et al. (Machado et al., 2019)
in a recent study prepared nanoemulsions stabilized by anionic surfactant poloxamer 188
which showed a high cellular uptake on MCF-7 (human breast adenocarcinoma cell line) and
HFF-1 (human foreskin fibroblast cell line) cells, as well as absence of cytotoxicity, thus
being classified as an effective and safe drug. They also reported that the use of
curcumin-nanoemulsions in photodynamic therapy resulted in a high phototoxic effect,
decreasing the proliferation of cells and increasing the reactive oxygen species (ROS)
generation in both cell lines. Their study suggested that curcumin nanoemulsions have a great
potential to treat breast cancer. Similarity, Guan et al. (Guan et al., 2017) evaluated curcumin
loaded nanoemulsions for prostate cancer. Curcumin nanoemulsions can enter the PC-3 cells
(human prostatic carcinoma cell line), and exhibit higher cytotoxicity than free curcumin. The
nanoemulsions present also a significantly prolonged biological activity and improved
therapeutic efficacy compared to free curcumin.
Some other studies reported the anti-cancer efficacy of curcumin nanoemulsions in animal
models. For instance, Ganta et al. (Ganta, Devalapally, & Amiji, 2010) designed curcumin and
paclitaxel-loaded nanoemulsions for treatment of ovarian adenocarcinoma in tumor-bearing
mice. The results revealed that curcumin downregulated the intracellular levels of intestinal
P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2), thereby increasing the
28
bioavailability of paclitaxel and inhibiting its metabolism. The coadministration of curcumin
and paclitaxel in nanoemulsions did not induce any acute toxicity, and showed significant
enhanced anti-tumor activity. Guerrero et al. (Guerrero et al., 2018) evaluated
curcumin-loaded nanoemulsions for the treatment of reincident tumor growth and metastasis.
The results showed that nanoformulation reduced in vitro cell proliferation, increased ROS
levels and permitted more persistent intracellular accumulation of curcumin, and prevented
migration and invasion of melanoma cells. In vivo experiments also showed that
curcumin-loaded nanoemulsions prevented melanoma reincidence and lung metastasis
post-surgery from remnant cells.
6. Conclusions and future trends
Curcumin is a natural compound with polyphenolic nature. This bioactive ingredient has been
proved to possess severial functional properties. Research performed to date has highlighted
the advantages of curcumin nanoencapsulation on its bioaccessibility and pharmacological
activities. This review comprehensively summarizes the main nanoencapsulations techniques.
The available scientific investigations indicate that over six nanoemulsions preparation
methods are used to encapsulate curcumin, including low-energy method (PIT and PIC),
high-energy method (HPH, microfluidization and ultrasonication) and intermediate energy
method (membrane emulsification). However, large-scale preparation of
curcumin-nanoemulsions, from a pilot scale to industrial exploitation, should gain increasing
attention.
Extensive studies have been performed to optimize and design effective nanoemulsion
systems with improved physicochemical stability and bioaccessibility. The key factors
affecting the stability and bioaccessibility of curcumin in nanoemulsion-based systems are the
nature and concentration of emulsifier, oil type and volume fraction and emulsifier-curcumin
interactions. LCT nanoemulsions tend to have better bioaccessibility than MCT
29
nanoemulsions. Additionally, the bioaccessibility of curcumin may increase with increasing
total lipid content when the lipid phase is fully digest. Furthermore, emulsifier type has an
influence on the curcumin bioaccessibility, by altering the droplet surface area within the
digestive tract, or by changing the ability of digestive enzymes to bind onto the emulsions
droplet surface. Nevertheless, emulsifier-curcumin interactions can reduce curcumin
bioaccessibility.
In addition, this review outlines pharmacological activity of curcumin-loaded nanoemulsions.
Pharmacological activity of curcumin-loaded nanoemulsions have been focused on the
bioassays in both in vitro (cell lines) and in vivo (mice and rats). They are advantageous over
curcumin solutions for a wide range of applications. Indeed, nanoencapsulation techniques
have been commonly applied to enhance the functional properties of curcumin, including
antioxidant, anti-inflammation and anti-cancer activities.
According to the applications section of this review, nanoformulations of curcumin will be
useful in the near future for different products. However, there is still a need for further
studies to give researchers and industries a broad range of deeper information. In particular,
further work is needed in areas such as toxicological evaluations and clinical applications of
curcumin as a nanomedicine for the prevention and treatment of various diseases or as a
nanoadditive in food products. Additionally, to obtain high entrapment efficiency and
narrowed particle size distribution, a new preparation technique with medium energy
membrane emulsification, could be investigated.
Conflicts of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the China Scholarship Council (No. 201808420225).
References
30
Abbas, S., Bashari, M., Akhtar, W., Li, W. W., & Zhang, X. (2014). Process optimization of
ultrasound-assisted curcumin nanoemulsions stabilized by OSA-modified starch. Ultrasonics
Sonochemistry, 21(4), 1265–1274. https://doi.org/10.1016/j.ultsonch.2013.12.017
Aditya, N. P., Aditya, S., Yang, H., Kim, H. W., Park, S. O., & Ko, S. (2015). Co-delivery of
hydrophobic curcumin and hydrophilic catechin by a water-in-oil-in-water double emulsion.
Food Chemistry, 173, 7–13. https://doi.org/10.1016/j.foodchem.2014.09.131
Ahmed, K., Li, Y., McClements, D. J., & Xiao, H. (2012). Nanoemulsion- and emulsion-based
delivery systems for curcumin: Encapsulation and release properties. Food Chemistry, 132(2),
799–807. https://doi.org/10.1016/j.foodchem.2011.11.039
Alliod, O., Messager, L., Fessi, H., Dupin, D., & Charcosset, C. (2019). Influence of viscosity for
oil-in-water and water-in-oil nanoemulsions production by SPG premix membrane
emulsification. Chemical Engineering Research and Design, 142, 87–99.
https://doi.org/10.1016/j.cherd.2018.11.027
Alliod, O., Valour, J.-P., Urbaniak, S., Fessi, H., Dupin, D., & Charcosset, C. (2018). Preparation of
oil-in-water nanoemulsions at large-scale using premix membrane emulsification and Shirasu
Porous Glass (SPG) membranes. Colloids and Surfaces A: Physicochemical and Engineering
Aspects, 557, 76–84. https://doi.org/10.1016/j.colsurfa.2018.04.045
Almeida, M. C., Sampaio, G. R., Bastos, D. H. M., & Villavicencio, A. L. C. H. (2018). Effect of
gamma radiation processing on turmeric: Antioxidant activity and curcumin content.
Radiation Physics and Chemistry, 152, 12–16.
https://doi.org/10.1016/j.radphyschem.2018.07.008
Anand, P., Kunnumakkara, A. B., Newman, R. A., & Aggarwal, B. B. (2007). Bioavailability of
Curcumin: Problems and Promises. Molecular Pharmaceutics, 4(6), 807–818.
https://doi.org/10.1021/mp700113r
Antunes, L. M. G., Araújo, M. C. P., Darin, J. D. C., & Bianchi, M. de L. P. (2000). Effects of the
antioxidants curcumin and vitamin C on cisplatin-induced clastogenesis in Wistar rat bone
marrow cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis,
465(1–2), 131–137. https://doi.org/10.1016/S1383-5718(99)00220-X
Araiza-Calahorra, A., Akhtar, M., & Sarkar, A. (2018). Recent advances in emulsion-based delivery
approaches for curcumin: From encapsulation to bioaccessibility. Trends in Food Science &
Technology, 71, 155–169. https://doi.org/10.1016/j.tifs.2017.11.009
Arkoumanis, P. G., Norton, I. T., & Spyropoulos, F. (2019). Pickering particle and emulsifier
co-stabilised emulsions produced via rotating membrane emulsification. Colloids and Surfaces
A: Physicochemical and Engineering Aspects, 568, 481–492.
https://doi.org/10.1016/j.colsurfa.2019.02.036
Arora, R., Kuhad, A., Kaur, I. P., & Chopra, K. (2015). Curcumin loaded solid lipid nanoparticles
ameliorate adjuvant-induced arthritis in rats. European Journal of Pain, 19(7), 940–952.
https://doi.org/10.1002/ejp.620
Artiga-Artigas, M., Lanjari-Pérez, Y., & Martín-Belloso, O. (2018). Curcumin-loaded nanoemulsions
stability as affected by the nature and concentration of surfactant. Food Chemistry, 266,
466–474. https://doi.org/10.1016/j.foodchem.2018.06.043
Bai, L., Huan, S., Gu, J., & McClements, D. J. (2016). Fabrication of oil-in-water nanoemulsions by
dual-channel microfluidization using natural emulsifiers: Saponins, phospholipids, proteins,
31
and polysaccharides. Food Hydrocolloids, 61, 703–711.
https://doi.org/10.1016/j.foodhyd.2016.06.035
Bai, L., & McClements, D. J. (2016). Development of microfluidization methods for efficient
production of concentrated nanoemulsions: Comparison of single- and dual-channel
microfluidizers. Journal of Colloid and Interface Science, 466, 206–212.
https://doi.org/10.1016/j.jcis.2015.12.039
Berendsen, R., Güell, C., & Ferrando, M. (2015). A procyanidin-rich extract encapsulated in
water-in-oil-in-water emulsions produced by premix membrane emulsification. Food
Hydrocolloids, 43, 636–648. https://doi.org/10.1016/j.foodhyd.2014.07.023
Bimonte, S., Barbieri, A., Leongito, M., Piccirillo, M., Giudice, A., Pivonello, C., … Izzo, F. (2016).
Curcumin AntiCancer Studies in Pancreatic Cancer. Nutrients, 8(7).
https://doi.org/10.3390/nu8070433
Borrin, T. R., Georges, E. L., Moraes, I. C. F., & Pinho, S. C. (2016). Curcumin-loaded nanoemulsions
produced by the emulsion inversion point (EIP) method: An evaluation of process parameters
and physico-chemical stability. Journal of Food Engineering, 169, 1–9.
https://doi.org/10.1016/j.jfoodeng.2015.08.012
Boscán, F., Barandiaran, M. J., & Paulis, M. (2018). From miniemulsion to nanoemulsion
polymerization of superhydrophobic monomers through low energy phase inversion
temperature. Journal of Industrial and Engineering Chemistry, 58, 1–8.
https://doi.org/10.1016/j.jiec.2017.08.052
Calderó, G., Montes, R., Llinàs, M., García-Celma, M. J., Porras, M., & Solans, C. (2016). Studies on
the formation of polymeric nano-emulsions obtained via low-energy emulsification and their
use as templates for drug delivery nanoparticle dispersions. Colloids and Surfaces B:
Biointerfaces, 145, 922–931. https://doi.org/10.1016/j.colsurfb.2016.06.013
Calligaris, S., Valoppi, F., Barba, L., Pizzale, L., Anese, M., Conte, L., & Nicoli, M. C. (2017).
Development of Transparent Curcumin Loaded Microemulsions by Phase Inversion
Temperature (PIT) Method: Effect of Lipid Type and Physical State on Curcumin Stability.
Food Biophysics, 12(1), 45–51. https://doi.org/10.1007/s11483-016-9461-4
Chen, Y.-C., Shie, M.-Y., Wu, Y.-H. A., Lee, K.-X. A., Wei, L.-J., & Shen, Y.-F. (2017).
Anti-inflammation performance of curcumin-loaded mesoporous calcium silicate cement.
Journal of the Formosan Medical Association, 116(9), 679–688.
https://doi.org/10.1016/j.jfma.2017.06.005
Chuacharoen, T., & Sabliov, C. M. (2019). Comparative effects of curcumin when delivered in a
nanoemulsion or nanoparticle form for food applications: Study on stability and lipid
oxidation inhibition. LWT, 113, 108319. https://doi.org/10.1016/j.lwt.2019.108319
Chuesiang, P., Siripatrawan, U., Sanguandeekul, R., Yang, J. S., McClements, D. J., &
McLandsborough, L. (2019). Antimicrobial activity and chemical stability of cinnamon oil in
oil-in-water nanoemulsions fabricated using the phase inversion temperature method. LWT.
https://doi.org/10.1016/j.lwt.2019.03.012
de Oliveira Honse, S., Kashefi, K., Charin, R. M., Tavares, F. W., Pinto, J. C., & Nele, M. (2018).
Emulsion phase inversion of model and crude oil systems detected by near-infrared
spectroscopy and principal component analysis. Colloids and Surfaces A: Physicochemical
and Engineering Aspects, 538, 565–573. https://doi.org/10.1016/j.colsurfa.2017.11.028
32
de Souza Ferreira, S. B., & Bruschi, M. L. (2019). Improving the bioavailability of curcumin: is
micro/nanoencapsulation the key? Therapeutic Delivery, 10(2), 83–86.
https://doi.org/10.4155/tde-2018-0075
Dhillon, N., Aggarwal, B. B., Newman, R. A., Wolff, R. A., Kunnumakkara, A. B., Abbruzzese, J.
L., … Kurzrock, R. (2008). Phase II Trial of Curcumin in Patients with Advanced Pancreatic
Cancer. Clinical Cancer Research, 14(14), 4491–4499.
https://doi.org/10.1158/1078-0432.CCR-08-0024
Eybl, V., Kotyzova, D., & Koutensky, J. (2006). Comparative study of natural antioxidants – curcumin,
resveratrol and melatonin – in cadmium-induced oxidative damage in mice. Toxicology,
225(2), 150–156. https://doi.org/10.1016/j.tox.2006.05.011
Ganta, S., Devalapally, H., & Amiji, M. (2010). Curcumin Enhances Oral Bioavailability and
Anti-Tumor Therapeutic Efficacy of Paclitaxel upon Administration in Nanoemulsion
Formulation. Journal of Pharmaceutical Sciences, 99(11), 4630–4641.
https://doi.org/10.1002/jps.22157
Gehrmann, S., & Bunjes, H. (2016). Instrumented small scale extruder to investigate the influence of
process parameters during premix membrane emulsification. Chemical Engineering Journal,
284, 716–723. https://doi.org/10.1016/j.cej.2015.09.022
Gehrmann, S., & Bunjes, H. (2017). Preparation of Nanoemulsions by Premix Membrane
Emulsification: Which Parameters Have a Significant Influence on the Resulting Particle Size?
Journal of Pharmaceutical Sciences, 106(8), 2068–2076.
https://doi.org/10.1016/j.xphs.2017.04.066
Ghasemi, F., Shafiee, M., Banikazemi, Z., Pourhanifeh, M. H., Khanbabaei, H., Shamshirian, A., …
Mirzaei, H. (2019). Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer
cells. Pathology - Research and Practice, 152556. https://doi.org/10.1016/j.prp.2019.152556
Ghosh, S., Banerjee, S., & Sil, P. C. (2015). The beneficial role of curcumin on inflammation, diabetes
and neurodegenerative disease: A recent update. Food and Chemical Toxicology, 83, 111–124.
https://doi.org/10.1016/j.fct.2015.05.022
Golding, M., Wooster, T. J., Day, L., Xu, M., Lundin, L., Keogh, J., & Clifton, P. (2011). Impact of
gastric structuring on the lipolysis of emulsified lipids. Soft Matter, 7(7), 3513.
https://doi.org/10.1039/c0sm01227k
Guan, Y., Zhou, S., Zhang, Y., Wang, J., Tian, Y., Jia, Y., & Sun, Y. (2017). Therapeutic effects of
curcumin nanoemulsions on prostate cancer. Journal of Huazhong University of Science and
Technology [Medical Sciences], 37(3), 371–378. https://doi.org/10.1007/s11596-017-1742-8
Guerrero, S., Inostroza-Riquelme, M., Contreras-Orellana, P., Diaz-Garcia, V., Lara, P., Vivanco-Palma,
A., … Oyarzun-Ampuero, F. (2018). Curcumin-loaded nanoemulsion: a new safe and effective
formulation to prevent tumor reincidence and metastasis. Nanoscale, 10(47), 22612–22622.
https://doi.org/10.1039/C8NR06173D
Güran, M., Şanlıtürk, G., Kerküklü, N. R., Altundağ, E. M., & Süha Yalçın, A. (2019). Combined
effects of quercetin and curcumin on anti-inflammatory and antimicrobial parameters in vitro.
European Journal of Pharmacology, 859, 172486.
https://doi.org/10.1016/j.ejphar.2019.172486
Hasan, S. T., Zingg, J.-M., Kwan, P., Noble, T., Smith, D., & Meydani, M. (2014). Curcumin
modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor
33
deficient mice. Atherosclerosis, 232(1), 40–51.
https://doi.org/10.1016/j.atherosclerosis.2013.10.016
Hashim, A. F., Hamed, S. F., Hay, H. A., Abd-Elsalam, K. A., Golonka, I., Musiał, W., & El-Sherbiny,
I. M. (2019). Antioxidant and antibacterial activities of omega-3 rich oils/curcumin
nanoemulsions loaded in chitosan and alginate-based microbeads. International Journal of
Biological Macromolecules, S0141813019340760.
https://doi.org/10.1016/j.ijbiomac.2019.08.085
Huang, X., Huang, X., Gong, Y., Xiao, H., McClements, D. J., & Hu, K. (2016). Enhancement of
curcumin water dispersibility and antioxidant activity using core–shell protein–polysaccharide
nanoparticles. Food Research International, 87, 1–9.
https://doi.org/10.1016/j.foodres.2016.06.009
Hur, S. J., Decker, E. A., & McClements, D. J. (2009). Influence of initial emulsifier type on
microstructural changes occurring in emulsified lipids during in vitro digestion. Food
Chemistry, 114(1), 253–262. https://doi.org/10.1016/j.foodchem.2008.09.069
Hussain, Z., Thu, H. E., Amjad, M. W., Hussain, F., Ahmed, T. A., & Khan, S. (2017). Exploring
recent developments to improve antioxidant, anti-inflammatory and antimicrobial efficacy of
curcumin: A review of new trends and future perspectives. Materials Science and Engineering:
C, 77, 1316–1326. https://doi.org/10.1016/j.msec.2017.03.226
Hussain, Z., Thu, H. E., Ng, S.-F., Khan, S., & Katas, H. (2017). Nanoencapsulation, an efficient and
promising approach to maximize wound healing efficacy of curcumin: A review of new trends
and state-of-the-art. Colloids and Surfaces B: Biointerfaces, 150, 223–241.
https://doi.org/10.1016/j.colsurfb.2016.11.036
Jafari, S. M., Assadpoor, E., He, Y., & Bhandari, B. (2008). Re-coalescence of emulsion droplets
during high-energy emulsification. Food Hydrocolloids, 22(7), 1191–1202.
https://doi.org/10.1016/j.foodhyd.2007.09.006
Jagetia, G. C., & Rajanikant, G. K. (2012). Acceleration of wound repair by curcumin in the excision
wound of mice exposed to different doses of fractionated γ radiation. International Wound
Journal, 9(1), 76–92. https://doi.org/10.1111/j.1742-481X.2011.00848.x
Jakubek, M., Kejík, Z., Kaplánek, R., Hromádka, R., Šandriková, V., Sýkora, D., … Král, V. (2019).
Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer.
Biomedicine & Pharmacotherapy, 118, 109278. https://doi.org/10.1016/j.biopha.2019.109278
Jamwal, R. (2018). Bioavailable curcumin formulations: A review of pharmacokinetic studies in
healthy volunteers. Journal of Integrative Medicine, 16(6), 367–374.
https://doi.org/10.1016/j.joim.2018.07.001
Jiang, H., Wang, Z., Wang, Y., Xie, K., Zhang, Q., Luan, Q., … Liu, D. (2013). Antidepressant-like
effects of curcumin in chronic mild stress of rats: Involvement of its anti-inflammatory action.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 47, 33–39.
https://doi.org/10.1016/j.pnpbp.2013.07.009
Jintapattanakit, A., Hasan, H. M., & Junyaprasert, V. B. (2018). Vegetable oil-based nanoemulsions
containing curcuminoids: Formation optimization by phase inversion temperature method.
Journal of Drug Delivery Science and Technology, 44, 289–297.
https://doi.org/10.1016/j.jddst.2017.12.018
Joseph, S., & Bunjes, H. (2012). Preparation of Nanoemulsions and Solid Lipid Nanoparticles by
34
Premix Membrane Emulsification. Journal of Pharmaceutical Sciences, 101(7), 2479–2489.
https://doi.org/10.1002/jps.23163
Joung, H. J., Choi, M.-J., Kim, J. T., Park, S. H., Park, H. J., & Shin, G. H. (2016). Development of
Food-Grade Curcumin Nanoemulsion and its Potential Application to Food Beverage System:
Antioxidant Property and In Vitro Digestion. Journal of Food Science, 81(3), N745–N753.
https://doi.org/10.1111/1750-3841.13224
Kant, V., Gopal, A., Kumar, D., Pathak, N. N., Ram, M., Jangir, B. L., … Kumar, D. (2015).
Curcumin-induced angiogenesis hastens wound healing in diabetic rats. Journal of Surgical
Research, 193(2), 978–988. https://doi.org/10.1016/j.jss.2014.10.019
Kharat, M., Zhang, G., & McClements, D. J. (2018). Stability of curcumin in oil-in-water emulsions:
Impact of emulsifier type and concentration on chemical degradation. Food Research
International, 111, 178–186. https://doi.org/10.1016/j.foodres.2018.05.021
Liu, H.-T., & Ho, Y.-S. (2018). Anticancer effect of curcumin on breast cancer and stem cells. Food
Science and Human Wellness, 7(2), 134–137. https://doi.org/10.1016/j.fshw.2018.06.001
Lv, H., Liu, J., Wang, L., Zhang, H., Yu, S., Li, Z., … Wang, W. (2014). Ameliorating Effects of
Combined Curcumin and Desferrioxamine on 6-OHDA-Induced Rat Mode of Parkinson’s
Disease. Cell Biochemistry and Biophysics, 70(2), 1433–1438.
https://doi.org/10.1007/s12013-014-0077-3
Ma, P., Zeng, Q., Tai, K., He, X., Yao, Y., Hong, X., & Yuan, F. (2017). Preparation of
curcumin-loaded emulsion using high pressure homogenization: Impact of oil phase and
concentration on physicochemical stability. LWT, 84, 34–46.
https://doi.org/10.1016/j.lwt.2017.04.074
Machado, F. C., Adum de Matos, R. P., Primo, F. L., Tedesco, A. C., Rahal, P., & Calmon, M. F. (2019).
Effect of curcumin-nanoemulsion associated with photodynamic therapy in breast
adenocarcinoma cell line. Bioorganic & Medicinal Chemistry, 27(9), 1882–1890.
https://doi.org/10.1016/j.bmc.2019.03.044
Maestro, A., Solè, I., González, C., Solans, C., & Gutiérrez, J. M. (2008). Influence of the phase
behavior on the properties of ionic nanoemulsions prepared by the phase inversion
composition method. Journal of Colloid and Interface Science, 327(2), 433–439.
https://doi.org/10.1016/j.jcis.2008.07.059
Marczylo, T. H., Verschoyle, R. D., Cooke, D. N., Morazzoni, P., Steward, W. P., & Gescher, A. J.
(2007). Comparison of systemic availability of curcumin with that of curcumin formulated
with phosphatidylcholine. Cancer Chemotherapy and Pharmacology, 60(2), 171–177.
https://doi.org/10.1007/s00280-006-0355-x
Mashhadi, S., Javadian, H., Tyagi, I., Agarwal, S., & Gupta, V. K. (2016). The effect of Na2SO4
concentration in aqueous phase on the phase inversion temperature of lemon oil in water
nano-emulsions. Journal of Molecular Liquids, 215, 454–460.
https://doi.org/10.1016/j.molliq.2016.01.045
Mistry, P. H., Mohapatra, S. K., & Dash, A. K. (2012). Effect of high-pressure homogenization and
stabilizers on the physicochemical properties of curcumin-loaded glycerol
monooleate/chitosan nanostructures. Nanomedicine, 7(12), 1863–1876.
https://doi.org/10.2217/nnm.12.49
Modarres-Gheisari, S. M. M., Gavagsaz-Ghoachani, R., Malaki, M., Safarpour, P., & Zandi, M. (2019).
35
Ultrasonic nano-emulsification – A review. Ultrasonics Sonochemistry, 52, 88–105.
https://doi.org/10.1016/j.ultsonch.2018.11.005
Mohammadian, M., Salami, M., Momen, S., Alavi, F., & Emam-Djomeh, Z. (2019). Fabrication of
curcumin-loaded whey protein microgels: Structural properties, antioxidant activity, and in
vitro release behavior. LWT, 103, 94–100. https://doi.org/10.1016/j.lwt.2018.12.076
Mohanty, C., Das, M., & Sahoo, S. K. (2012). Sustained Wound Healing Activity of Curcumin Loaded
Oleic Acid Based Polymeric Bandage in a Rat Model. Molecular Pharmaceutics, 9(10),
2801–2811. https://doi.org/10.1021/mp300075u
Morsy, M. A., & El-Moselhy, M. A. (2013). Mechanisms of the Protective Effects of Curcumin against
Indomethacin-Induced Gastric Ulcer in Rats. Pharmacology, 91(5–6), 267–274.
https://doi.org/10.1159/000350190
Mourtas, S., Lazar, A. N., Markoutsa, E., Duyckaerts, C., & Antimisiaris, S. G. (2014).
Multifunctional nanoliposomes with curcumin–lipid derivative and brain targeting
functionality with potential applications for Alzheimer disease. European Journal of
Medicinal Chemistry, 80, 175–183. https://doi.org/10.1016/j.ejmech.2014.04.050
Mun, S.-H., Joung, D.-K., Kim, Y.-S., Kang, O.-H., Kim, S.-B., Seo, Y.-S., … Kwon, D.-Y. (2013).
Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus
aureus. Phytomedicine, 20(8–9), 714–718. https://doi.org/10.1016/j.phymed.2013.02.006
Nazir, A., Schroën, K., & Boom, R. (2013). The effect of pore geometry on premix membrane
emulsification using nickel sieves having uniform pores. Chemical Engineering Science, 93,
173–180. https://doi.org/10.1016/j.ces.2013.01.029
Nguyen, M.-H., Lee, S. E., Tran, T.-T., Bui, C.-B., Nguyen, T.-H.-N., Vu, N.-B.-D., … Hadinoto, K.
(2019). A simple strategy to enhance the in vivo wound-healing activity of curcumin in the
form of self-assembled nanoparticle complex of curcumin and oligochitosan. Materials
Science and Engineering: C, 98, 54–64. https://doi.org/10.1016/j.msec.2018.12.091
Páez-Hernández, G., Mondragón-Cortez, P., & Espinosa-Andrews, H. (2019). Developing curcumin
nanoemulsions by high-intensity methods: Impact of ultrasonication and microfluidization
parameters. LWT. https://doi.org/10.1016/j.lwt.2019.05.012
Pan, M.-H., Huang, T.-M., & Lin, J.-K. (1999). Biotransformation of Curcumin Through Reduction
and Glucuronidation in Mice. Drug Metabolism and Disposition, 27(4), 486–494.
Park, H. R., Rho, S.-J., & Kim, Y.-R. (2019). Solubility, stability, and bioaccessibility improvement of
curcumin encapsulated using 4-α-glucanotransferase-modified rice starch with reversible
pH-induced aggregation property. Food Hydrocolloids, 95, 19–32.
https://doi.org/10.1016/j.foodhyd.2019.04.012
Park, S. J., Garcia, C. V., Shin, G. H., & Kim, J. T. (2018). Improvement of curcuminoid
bioaccessibility from turmeric by a nanostructured lipid carrier system. Food Chemistry, 251,
51–57. https://doi.org/10.1016/j.foodchem.2018.01.071
Peng, J., Dong, W., Li, L., Xu, J., Jin, D., Xia, X., & Liu, Y. (2015). Effect of high-pressure
homogenization preparation on mean globule size and large-diameter tail of oil-in-water
injectable emulsions. Journal of Food and Drug Analysis, 23(4), 828–835.
https://doi.org/10.1016/j.jfda.2015.04.004
Phan, T.-T., See, P., Lee, S.-T., & Chan, S.-Y. (2001). Protective Effects of Curcumin against Oxidative
Damage on Skin Cells In Vitro: Its Implication for Wound Healing: The Journal of Trauma:
36
Injury, Infection, and Critical Care, 51(5), 927–931.
https://doi.org/10.1097/00005373-200111000-00017
Pinheiro, A. C., Coimbra, M. A., & Vicente, A. A. (2016). In vitro behaviour of curcumin
nanoemulsions stabilized by biopolymer emulsifiers – Effect of interfacial composition. Food
Hydrocolloids, 52, 460–467. https://doi.org/10.1016/j.foodhyd.2015.07.025
Pinheiro, A. C., Lad, M., Silva, H. D., Coimbra, M. A., Boland, M., & Vicente, A. A. (2013).
Unravelling the behaviour of curcumin nanoemulsions during in vitro digestion: effect of the
surface charge. Soft Matter, 9(11), 3147. https://doi.org/10.1039/c3sm27527b
Prasad, S., Gupta, S. C., Tyagi, A. K., & Aggarwal, B. B. (2014). Curcumin, a component of golden
spice: From bedside to bench and back. Biotechnology Advances, 32(6), 1053–1064.
https://doi.org/10.1016/j.biotechadv.2014.04.004
Priyadarsini, K. I. (2014). The Chemistry of Curcumin: From Extraction to Therapeutic Agent.
Molecules, 19(12), 20091–20112. https://doi.org/10.3390/molecules191220091
Rafiee, Z., Nejatian, M., Daeihamed, M., & Jafari, S. M. (2019). Application of curcumin-loaded
nanocarriers for food, drug and cosmetic purposes. Trends in Food Science & Technology, 88,
445–458. https://doi.org/10.1016/j.tifs.2019.04.017
Rajasekaran, S. A. (2011). Therapeutic potential of curcumin in gastrointestinal diseases. World
Journal of Gastrointestinal Pathophysiology, 2(1), 1. https://doi.org/10.4291/wjgp.v2.i1.1
Rakariyatham, K., Du, Z., Yuan, B., Gao, Z., Song, M., Pan, C., … Xiao, H. (2019). Inhibitory effects
of 7,7′-bromo-curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation.
European Journal of Pharmacology, 858, 172479.
https://doi.org/10.1016/j.ejphar.2019.172479
Raviadaran, R., Chandran, D., Shin, L. H., & Manickam, S. (2018). Optimization of palm oil in water
nano-emulsion with curcumin using microfluidizer and response surface methodology. LWT,
96, 58–65. https://doi.org/10.1016/j.lwt.2018.05.022
Ren, G., Sun, Z., Wang, Z., Zheng, X., Xu, Z., & Sun, D. (2019). Nanoemulsion formation by the
phase inversion temperature method using polyoxypropylene surfactants. Journal of Colloid
and Interface Science, 540, 177–184. https://doi.org/10.1016/j.jcis.2019.01.018
Rivera-Mancía, S., Lozada-García, M. C., & Pedraza-Chaverri, J. (2015). Experimental evidence for
curcumin and its analogs for management of diabetes mellitus and its associated complications.
European Journal of Pharmacology, 756, 30–37. https://doi.org/10.1016/j.ejphar.2015.02.045
Rodrigues, F. C., Anil Kumar, N. V., & Thakur, G. (2019). Developments in the anticancer activity of
structurally modified curcumin: An up-to-date review. European Journal of Medicinal
Chemistry, 177, 76–104. https://doi.org/10.1016/j.ejmech.2019.04.058
Roger, K. (2016). Nanoemulsification in the vicinity of phase inversion: Disruption of bicontinuous
structures in oil/surfactant/water systems. Current Opinion in Colloid & Interface Science, 25,
120–128. https://doi.org/10.1016/j.cocis.2016.09.015
Sah, A., Jha, R., Sah, P., Shah, D., & Yadav, S. (2013). Turmeric (curcumin) remedies gastroprotective
action. Pharmacognosy Reviews, 7(1), 42. https://doi.org/10.4103/0973-7847.112843
Sahebkar, A. (2015). Dual effect of curcumin in preventing atherosclerosis: the potential role of
pro-oxidant–antioxidant mechanisms. Natural Product Research, 29(6), 491–492.
https://doi.org/10.1080/14786419.2014.956212
Sahne, F., Mohammadi, M., Najafpour, G. D., & Moghadamnia, A. A. (2017). Enzyme-assisted ionic
37
liquid extraction of bioactive compound from turmeric ( Curcuma longa L.): Isolation,
purification and analysis of curcumin. Industrial Crops and Products, 95, 686–694.
https://doi.org/10.1016/j.indcrop.2016.11.037
Salvia-Trujillo, L., Martín-Belloso, O., & McClements, D. (2016). Excipient Nanoemulsions for
Improving Oral Bioavailability of Bioactives. Nanomaterials, 6(1), 17.
https://doi.org/10.3390/nano6010017
Sanidad, K. Z., Sukamtoh, E., Xiao, H., McClements, D. J., & Zhang, G. (2019). Curcumin: Recent
Advances in the Development of Strategies to Improve Oral Bioavailability. Annual Review of
Food Science and Technology, 10(1), 597–617.
https://doi.org/10.1146/annurev-food-032818-121738
Santos, J., Vladisavljević, G. T., Holdich, R. G., Dragosavac, M. M., & Muñoz, J. (2015). Controlled
production of eco-friendly emulsions using direct and premix membrane emulsification.
Chemical Engineering Research and Design, 98, 59–69.
https://doi.org/10.1016/j.cherd.2015.04.009
Sari, T. P., Mann, B., Kumar, R., Singh, R. R. B., Sharma, R., Bhardwaj, M., & Athira, S. (2015).
Preparation and characterization of nanoemulsion encapsulating curcumin. Food
Hydrocolloids, 43, 540–546. https://doi.org/10.1016/j.foodhyd.2014.07.011
Sarkar, A., Goh, K. K. T., Singh, R. P., & Singh, H. (2009). Behaviour of an oil-in-water emulsion
stabilized by β-lactoglobulin in an in vitro gastric model. Food Hydrocolloids, 23(6),
1563–1569. https://doi.org/10.1016/j.foodhyd.2008.10.014
Sasaki, H., Sunagawa, Y., Takahashi, K., Imaizumi, A., Fukuda, H., Hashimoto, T., … Morimoto, T.
(2011). Innovative Preparation of Curcumin for Improved Oral Bioavailability. Biological &
Pharmaceutical Bulletin, 34(5), 660–665. https://doi.org/10.1248/bpb.34.660
Shah, B. R., Zhang, C., Li, Y., & Li, B. (2016). Bioaccessibility and antioxidant activity of curcumin
after encapsulated by nano and Pickering emulsion based on chitosan-tripolyphosphate
nanoparticles. Food Research International, 89, 399–407.
https://doi.org/10.1016/j.foodres.2016.08.022
Sharif, A. A. M., Astaraki, A. M., Azar, P. A., Khorrami, S. A., & Moradi, S. (2012). The effect of
NaCl and Na2SO4 concentration in aqueous phase on the phase inversion temperature O/W
nanoemulsions. Arabian Journal of Chemistry, 5(1), 41–44.
https://doi.org/10.1016/j.arabjc.2010.07.021
Sharma, R. A., McLelland, H. R., Hill, K. A., Ireson, C. R., Euden, S. A., Manson, M. M., … Steward,
W. P. (n.d.). Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in
Patients with Colorectal Cancer. 8.
Silva, H. D., Beldíková, E., Poejo, J., Abrunhosa, L., Serra, A. T., Duarte, C. M. M., … Vicente, A. A.
(2019). Evaluating the effect of chitosan layer on bioaccessibility and cellular uptake of
curcumin nanoemulsions. Journal of Food Engineering, 243, 89–100.
https://doi.org/10.1016/j.jfoodeng.2018.09.007
Silva, H. D., Poejo, J., Pinheiro, A. C., Donsì, F., Serra, A. T., Duarte, C. M. M., … Vicente, A. A.
(2018). Evaluating the behaviour of curcumin nanoemulsions and multilayer nanoemulsions
during dynamic in vitro digestion. Journal of Functional Foods, 48, 605–613.
https://doi.org/10.1016/j.jff.2018.08.002
Singh, M., Pandey, A., Karikari, C. A., Singh, G., & Rakheja, D. (2010). Cell cycle inhibition and
38
apoptosis induced by curcumin in Ewing sarcoma cell line SK-NEP-1. Medical Oncology,
27(4), 1096–1101. https://doi.org/10.1007/s12032-009-9341-6
Singh, Y., Meher, J. G., Raval, K., Khan, F. A., Chaurasia, M., Jain, N. K., & Chourasia, M. K. (2017).
Nanoemulsion: Concepts, development and applications in drug delivery. Journal of
Controlled Release, 252, 28–49. https://doi.org/10.1016/j.jconrel.2017.03.008
Solans, C., & Solé, I. (2012). Nano-emulsions: Formation by low-energy methods. Current Opinion in
Colloid & Interface Science, 17(5), 246–254. https://doi.org/10.1016/j.cocis.2012.07.003
Solè, I., Pey, C. M., Maestro, A., González, C., Porras, M., Solans, C., & Gutiérrez, J. M. (2010).
Nano-emulsions prepared by the phase inversion composition method: Preparation variables
and scale up. Journal of Colloid and Interface Science, 344(2), 417–423.
https://doi.org/10.1016/j.jcis.2009.11.046
Sorasitthiyanukarn, F. N., Muangnoi, C., Thaweesest, W., Rojsitthisak, P., & Rojsitthisak, P. (2019).
Enhanced cytotoxic, antioxidant and anti-inflammatory activities of curcumin diethyl
disuccinate using chitosan-tripolyphosphate nanoparticles. Journal of Drug Delivery Science
and Technology, 53, 101118. https://doi.org/10.1016/j.jddst.2019.06.015
Sun, J., Chen, F., Braun, C., Zhou, Y.-Q., Rittner, H., Tian, Y.-K., … Ye, D.-W. (2018). Role of
curcumin in the management of pathological pain. Phytomedicine, 48, 129–140.
https://doi.org/10.1016/j.phymed.2018.04.045
Teiten, M.-H., Gaascht, F., Eifes, S., Dicato, M., & Diederich, M. (2010). Chemopreventive potential
of curcumin in prostate cancer. Genes & Nutrition, 5(1), 61–74.
https://doi.org/10.1007/s12263-009-0152-3
Thomas, L., Zakir, F., Mirza, M. A., Anwer, M. K., Ahmad, F. J., & Iqbal, Z. (2017). Development of
Curcumin loaded chitosan polymer based nanoemulsion gel: In vitro, ex vivo evaluation and
in vivo wound healing studies. International Journal of Biological Macromolecules, 101,
569–579. https://doi.org/10.1016/j.ijbiomac.2017.03.066
Typek, R., Dawidowicz, A. L., Wianowska, D., Bernacik, K., Stankevič, M., & Gil, M. (2019).
Formation of aqueous and alcoholic adducts of curcumin during its extraction. Food
Chemistry, 276, 101–109. https://doi.org/10.1016/j.foodchem.2018.10.006
Wakte, P. S., Sachin, B. S., Patil, A. A., Mohato, D. M., Band, T. H., & Shinde, D. B. (2011).
Optimization of microwave, ultra-sonic and supercritical carbon dioxide assisted extraction
techniques for curcumin from Curcuma longa. Separation and Purification Technology, 79(1),
50–55. https://doi.org/10.1016/j.seppur.2011.03.010
Wang, B., Liu, X., Teng, Y., Yu, T., Chen, J., Hu, Y., … Shen, Y. (2017). Improving anti-melanoma
effect of curcumin by biodegradable nanoparticles. Oncotarget, 8(65).
https://doi.org/10.18632/oncotarget.20585
Wang, X., Jiang, Y., Wang, Y.-W., Huang, M.-T., Ho, C.-T., & Huang, Q. (2008). Enhancing
anti-inflammation activity of curcumin through O/W nanoemulsions. Food Chemistry, 108(2),
419–424. https://doi.org/10.1016/j.foodchem.2007.10.086
Xu, G., Wang, C., & Yao, P. (2017). Stable emulsion produced from casein and soy polysaccharide
compacted complex for protection and oral delivery of curcumin. Food Hydrocolloids, 71,
108–117. https://doi.org/10.1016/j.foodhyd.2017.05.010
Yang, H. J., Cho, W. G., & Park, S. N. (2009). Stability of oil-in-water nano-emulsions prepared using
the phase inversion composition method. Journal of Industrial and Engineering Chemistry,
39
15(3), 331–335. https://doi.org/10.1016/j.jiec.2009.01.001
Yang, Y., Marshall-Breton, C., Leser, M. E., Sher, A. A., & McClements, D. J. (2012). Fabrication of
ultrafine edible emulsions: Comparison of high-energy and low-energy homogenization
methods. Food Hydrocolloids, 29(2), 398–406. https://doi.org/10.1016/j.foodhyd.2012.04.009
Ye, Z., Cao, C., Liu, Y., Cao, P., & Li, Q. (2018). Triglyceride Structure Modulates Gastrointestinal
Digestion Fates of Lipids: A Comparative Study between Typical Edible Oils and
Triglycerides Using Fully Designed in Vitro Digestion Model. Journal of Agricultural and
Food Chemistry, 66(24), 6227–6238. https://doi.org/10.1021/acs.jafc.8b01577
Yu, L., Li, C., Xu, J., Hao, J., & Sun, D. (2012). Highly Stable Concentrated Nanoemulsions by the
Phase Inversion Composition Method at Elevated Temperature. Langmuir, 28(41),
14547–14552. https://doi.org/10.1021/la302995a
Zheng, B., Peng, S., Zhang, X., & McClements, D. J. (2018). Impact of Delivery System Type on
Curcumin Bioaccessibility: Comparison of Curcumin-Loaded Nanoemulsions with
Commercial Curcumin Supplements. Journal of Agricultural and Food Chemistry, 66(41),
10816–10826. https://doi.org/10.1021/acs.jafc.8b03174
Zheng, B., Zhang, Z., Chen, F., Luo, X., & McClements, D. J. (2017). Impact of delivery system type
on curcumin stability: Comparison of curcumin degradation in aqueous solutions, emulsions,
and hydrogel beads. Food Hydrocolloids, 71, 187–197.
https://doi.org/10.1016/j.foodhyd.2017.05.022
40
Fig. 1. Structural representation of keto (top) and enol form (bottom) of curcumin.
Fig. 2. Schematic illustration of PIT (a) and PIC (b).
oHoH
oCH3 oCH3
o o
oHoH
oCH3 oCH3
o oH
Keto Form
Enol Form
41
Fig. 3. Schematic illustration of ultrasonication (a), HPH (b), two-step single-channel
microfluidization (c) and one-step dual-channel microfluidization (d), DME (e) and PME (f).
42
Table 1
Summary of the methods of preparation of curcumin-loaded nanoemulsions.
Methods Surfactant(s) (w/w%) Oil (w/w%) Curcumin dispersion method and
concentration (w/w%) Emulsification process
DZ (nm)
PDI
ZP
(mV) References
PIT
RH40 (10~20a ) Coconut oil (8.3
a)
Magnetic stirring (60 °C, 60 min), then
shaken (30 °C, 24 h)/0.008~0.167a
Magnetic stirring (3 temperature cycles
90-60-90-60-90-75°C)
33~78
(PDI ≤ 0.1) -6.5~2.6
Jintapattanakit et al.
(2018)
Tween 80 (5~40a)
Extra virgin olive
(1~9a)
Magnetic stirring (in the dark under
nitrogen)/ 0.5a
Magnetic stirring (70-90-20°C) 100-1000 − Calligaris et al. (2017)
Ultrasonication
Hydroxylated soy lecithin
(1.44~14.4b)
MCT, Grapeseed oil,
or Olive oil (2~20b)
Curcumin dissolved in ethanol, then
oil, evaporation of ethanol/10c
High-speed mixer (6,500 rpm, 4 min),
Ultrasonication (130 w and 750 w, 30 min)
≤ 600
(PDI ≤ 0.35) ≤ -50
Páez-Hernández et al.
(2019)
Purity Gum 2000, Hi-Cap
100 or Purity Gum Ultra
(0.5~15a)
MCT (2~14b)
Magnetic stirring (100 °C, 7 min)
/1~15c
High-speed mixer (14000 rpm, 2 min),
High-intensity sonication (120-1200 w, 1-13
min)
≤ 260
(PDI ≤ 0.2) ≤ -25 Abbas et al. (2014)
whey protein
concentrate-70 (0.5a) and
Tween-80 (2a)
MCT (2a) -/40
c
Magnetic stirring (room temperature),
Sonification
141.6
(PDI = 0.27) -6.9 Sari et al. (2015)
HPH
Polyvinyl alcohol (0.5a) or
poloxamer (0.1a)
Glyceryl monooleate
(1.4a)
Curcumin dissolved in acetone/4, 8a
Magnetic stirring (7,000 rpm, 2 min), HPH
(15,000 psi, 10 cycles) ≤ 400 0~20 Mistry et al. (2012)
Tween 80 (2a), lecithin (5
a),
acacia powder (5a), whey
protein (5a)
MCT, linseed oil or
canola oil (5~30a)
Ultrasonication/12c High-speed blender (10,000 rpm, 6 min), HPH
(60MPa, 3 cycles) 200~4000 -60~0 Ma et al. (2017)
When protein isolate (1.5a ) MCT (10
a) 70 °C/0.1
a
Ultra-Turrax homogenizer (5000 rpm, 2 min),
HPH (40 bars, 20 cycles)
186
(PDI = 0.124) -51.9 Silva et al. (2019)
Microfluidization
Tween 80 (0.5~1a) Palm olein oil (20
a)
Curcumin and oil dissolved in
ethanol/1a
High-speed homogenizer (7,000 rev/min, 1h),
Microfluidizer (350-450 bar, 1-12 cycles)
≤ 270
(PDI ≤ 0.3) -43−-31
Raviadaran et al.
(2018)
Hydroxylated soy lecithin
(1.44~14.4 b)
MCT, Grapeseed oil
and Olive oil (2~20b)
Curcumin dissolved in ethanol, then
oil, evaporation of ethanol/10c
High-speed mixer (6500 rpm, 4 min),
Microfluidizer (70 or 140 MPa, 1-10 cycles)
≤ 200
(PDI ≤ 0.38) ≤ -50
Páez-Hernández et
al. (2019)
Tween 20, Lecithin or
Sucrose
monopalmitate (0.5~2a)
Corn oil (0.5a)
Magnetic stirring (room temperature,
24 h)/0.4a
High-shear homogenizer (11,000 rpm, 2 min),
Microfluidizer (150 MPa, 5 cycles)
≤400
(PDI≤ 0.54) ≤-37
Artiga-Artigas et al.
(2018)
a w/w%;
b v/v%;
c mg mL
−1.
Abbreviations: DZ, droplet size; ZP, zeta potential; PDI, polydispersity index.
43
Table 2
Composition and formation of nanoemulsions for delivery of curcumin.
Surfactant(s) (w/w%) Oil (w/w%) Curcumin dispersion method and
concentration (w/w%)
Emulsification process DZ (nm)
PDI
ZP (mV) References
Tween 80 (1%a) Corn oil (1
a) Curcumin dissolved in stock
emulsions (85 °C, 2 h)/3c
High shear mixer (2 min),
HPH (12,000 psi, 5 cycles)
270
(PDI ≤ 0.38)
-20.3(pH 7)
+0.2(pH 3)
Zheng et al.
(2017)
Soy soluble polysaccharide:casein
= 1:1 (20c)
MCT : Vitamin E
= 1:1 (16.7b)
Curcumin dissolved in Vitamin E
and MCT (-)/1.7c
Homogenizer (10,000 rpm, 1 min), HPH
(800 bar, 4 min)
300~500
-50~10
Xu et al.
(2017)
Gun arabic, saponins, Tween 80
and caseinate (0.5~10a)
MCT(9a) Magnetic stirring (60 °C, 2 h), then
sonicated (20 min) /0.1a
High-speed blender (2 min),
Microfluidization (12,000 psi, 5 cycles)
~2000 -65.3~-2.2 Kharat et al.
(2018)
Tween 20, Lecithin or Sucrose
monopalmitate (0.5~2a)
Corn oil (0.5a)
Magnetic stirring (room
temperature, 24 h)/0.4a
High-shear homogenizer (11,000 rpm, 2
min), Microfluidization (150 MPa, 5
cycles)
≤400 (PDI ≤ 0.54) ≤-37 Artiga-Artigas
et al. (2018)
Polyglycerol polyricinoleate (0.6a)
and Tween 80 (1a)
Olive oil (18.75a) Magnetic stirring (15 min)/0.1
d
Magnetic stirrer(1500 rpm, 2 min),
Sonication(20 kHz, 4 min) for W/O
nanoemulsions, and then added to the
secondary water phase using the same
process
<590 ≈-20 Aditya et al.
(2015)
Glycerol monostearate (3a) and
Tween 80 (1~20a)
MCT(−) Magnetic stirring (70°C, 2 h)/0.1a High-speed homogenization (5000 rpm,
1 min), Sonification (1~9min)
200~500
(0.2 < PDI < 0.8)
-15~-25 Park et al.
(2018)
Quillaja saponin (1a) Corn oil (5
a) Incubation (60°C, 2 h) or curcumin
dissolved in stock emulsions
(100 °C, 15 min or pH 12.5)/0.015a
High-speed blender (2 min), HPH
(12,000 psi, 5 cycles)
170~200
≈-45 Zheng et al.
(2018)
β-lactoglobulin (1a) Corn oil, MCT or
Tributyrin (10a)
Magnetic stirring (60°C, 10 min ),
sonication (20 min)/0.15a
High-speed blender (2 min), HPH (9000
psi, 5 cycles)
174, 181, 1981 and
182 (0.13<PDI<0.75)
− Ahmed et al.
(2012)
Span80:Tween80=1.5:8.5 (10a) MCT or LCT(5
a) Magnetic stirring (overnight )/0.1
a Magnetic string (room temperature, 15
min)
< 200 -4.26 or
-12.84
Shah et al.
(2016)
Tween 20, SDS or DTAB (0.5a) Corn oil (5
a) −/0.1
a High-speed blender (2 min),
Microfluidization (20,000 psi, 5 cycles)
124, 152 or 119 (PDI
= 0.42, 0.19, 0.22)
-1.03, -92.86
or -89.42
Pinheiro et al.
(2013)
Lactoferrin (2a) or lactoferrin (2
a)
/alginate (0.2 a)
Corn oil (5a) −/0.1
a High-speed homogenization (2 min),
HPH (20,000 psi, 20 cycles)
<500 27.47 or≈-30 Pinheiro et al.
(2016)
SDS (1a) or chitosan (0.06
a) /
alginate (0.02a) / SDS(1
a)
MCT(10b) (90°C, 30 min )/0.1
a High-speed homogenization (2 min),
HPH (15,000 psi, 20 cycles)
80 (PDI = 0.177) or
130 (PDI = 0.237)
-65.8 or 10.4 Sliva et al.
(2018) a w/w%;
b v/v%;
c mg mL
−1;
d w/v%.
Abbreviations: DZ, droplet size; ZP, zeta potential; PDI, polydispersity index.
44
Table 3
Examples of studies considering applications of curcumin nanoformulations.
Application Methods of preparation Study design Study outcome References
Anti-oxidant
Prepared by magnetic stirring and
sonification using MCT as oil, Tween
80 as surfactant and WPC-70 as
emulsifier
The total antioxidant activity was determined by
DPPH, and the GIT digest was analyzed for
release of curcumin.
The encapsulation not only preserved the antioxidant activity
but also slowed down the release of curcumin
Sari et al. (2015)
Prepared by HPH using MCT as oil,
Tween 80 and lecithin as surfactants
The stability of curcumin-nanocarriers was
addressed and applied to milk systems.
Curcumin-nanocarriers protected curcumin against
degradation and inhibited lipid oxidation.
Chuacharoen et
al. (2019)
Prepared by high-speed
homogenization and HPH using MCT
as oil, Tween 20 as emulsifier
Curcumin nanoemulsions were developed and
applied to commercial milk systems.
Curcumin nanoemulsions were significantly effective to
reduce lipid oxidation of milk during storage.
Joung et al.
(2016)
Anti-inflammatory
Prepared by high-speed
homogenization and HPH using MCT
as oil and Tween 20 as emulsifier
The anti-inflammatory activity of curcumin
nanoemulsions was studied in a mouse ear
inflammation model.
Curcumin nanoemulsions showed improved inhibition on the
edema of mouse ear, and such activity was further enhanced
when emulsions droplet sizes were reduced to below 100 nm.
Wang et al.
(2008)
Prepared using Labrafac PG +
Triacetin as oil, Tween 80 as a
surfactant and polyethylene glycol
(PEG 400) as a co-surfactant.
Ex-vivo permeation and deposition studies were
performed through rat skin, and wound-healing
activity was performed by incision wound model
in wistar rats.
Nanoemulsion can be used for loading curcumin for the
treatment of wound healing.
Thomas et al.
(2017)
Anti-cancer
Prepared by spontaneous
nanoemulsification method using
MCT and natural soy phospholipids as
oil, and poloxamer 188 as surfactant
The action of curcumin nanoemulsion used as a
photosensitizing agent in photodynamic therapy
in an in vitro breast cancer model, MCF-7 cells
was analyzed.
Curcumin-nanoemulsion had phototoxic effects, significantly
decreased the proliferation of MCF-7 cells and stimulating the
ROS production, demonstrating great potential for treatment
of breast cancer.
Machado et al.
(2019)
Prepared by self-microemulsifying
method using MCT as oil, cremophor
RH 40 as surfactant and glycerol as
co-surfactant.
Curcumin nanoemulsions and curumin against
prostate cancer cells (PC-3 cell) was evaluated.
Curcumin nanoemulsions exhibited an increased cytotoxicity
and cell uptake, a better therapeutic efficacy than free
curcumin. It can be used as an effective drug delivery system
to enhance the anticancer effect.
Guan et al. (2017)
Prepared by ultrasonication using
omega-3 fatty acid-rich flax-seed oil as
oil, egg yolk lecithin and deoxycholic
acid as surfactants
The effect of curcumin in oral bioavailability and
therapeutic efficacy of paclitaxel administered in
nanoemulsion to SKOV3 tumor-bearing nu/nu
mice was evaluated.
Paclitaxel administered in nanoemulsion to curcumin
pretreated mice did not induce any acute toxicity. The
combination could improve oral bioavailability and
therapeutic efficacy in ovarian adenocarcinoma.
Ganta et al.
(2010)
Prepared by spontaneous
nanoemulsification method using
The totoxicy of curcumin nanoemulsions in
different cell lines was determined, and the effect
Nanoformulation increased intracellular curcumin
accumulation and ROS formation, while preventing
Guerrero et al.
(2018)
45
Miglyol 812 as oil, Epikuron 145 V as
surfactants
on preventing post-surgery tumor reincidence
and metastasis in C57BL/6 mice was evaluated.
cell-migration and invasion in melanoma cells. It also prevent
reincident tumor growth and spontaneous lung metastasis in
mice.
1
1
Recommended